COMBINATION THERAPY FOR PROLIFERATIVE DISORDERS CROSS-REFERENCE [0001] This application claims the benefit of U. S. Provisional Patent Application Nos.

60/471,841, filed May 16,2003 ; 60/485, 474, filed July 8,2003 ; 60/514, 173, filed October 24, 2003; 60/511,280, filed October 14,2003 ; 60/511,415, filed October 14,2003 ; 60/511,259, filed October 14,2003, and 60/561,940, filed April 13,2004, each of which applications is incorporated herein by reference in their entirety.

FIELD OF THE INVENTION [0002] The present invention is in the field of treatment of proliferative disorders, including angiogenesis-mediated disorders, cancer, and fibrotic disorders.

BACKGROUND OF THE INVENTION [0003] The leading therapies for cancer are currently surgery, radiation and chemotherapy.

Chemotherapeutic approaches such as, antitumor antibiotics, alkylating agents, nitrosourea compounds, vinca alkaloids, steroid hormones, and anti-metabolites form the bulk of therapies available to oncologists. Despite advances in the field of cancer treatment, cancer remains a major health problem.

[0004] Current data indicate that fibrosis is not a static process; extracellular matrix is constantly being laid down and resorbed and the progressive accumulation of fibrous tissue is thought to represent a relative imbalance between pro-fibrotic processes and anti-fibrotic processes. If these processes are not properly regulated, the pathologic and progressive accumulation of collagen in the extracellular space as a result of a disordered wound healing process leads to replacement of normal cells by dense fibrous bands of protein, and results in fibrotic disease with disordered function in the affected organ (for example, impairment of respiratory function, impaired circulatory function via fibrotic changes in arterial walls, fibrotic degeneration of renal and liver function, degenerative musculoskeletal function, fibrotic degeneration of cardiac muscle or skeletal muscle, fibrotic degenerative changes in neuronal tissues in the central nervous system as well as the peripheral nervous system, etc.).

[0005] In addition to fibrotic disorders of the lung, liver and kidney, many other organs and tissues are susceptible to fibrotic degeneration. In particular, cardiac injury from hypoxia or ischemia, toxins, infectious agents, genetic etiologies, and structural disorders can lead to an inappropriate chronic wound healing process that results in fibrosis of cardiac tissue.

[0006] There is a need in the art for treating proliferative disorders, including fibrotic disorders, cancer, and angiogenic disorders. The present invention addresses this need.

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[0008] Al-Bayati et al. (2002) Biochem. Pharmacol. 64: 517-525; Shihab et al. (2002) Am. J : Transplant. 2: 111-119; Yu et al. (2002) Curr. Opinion Pharmacol. 2: 177-181; U. S. Patent Nos. 5,310, 562; 5,518, 729; 5,716, 632; and 6,090, 822.

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SUMMARY OF THE INVENTION [0011] The present invention provides methods of treating proliferative disorders, including angiogenesis-mediated disorders, cancer, and fibrotic disorders. In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor. The present invention further provides methods of treating fibrotic disorders. In some embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist; and a tumor necrosis factor (TNF) antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-ß) antagonist. In other embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist.

FEATURES OF THE INVENTION Type II interferon agonist and Type I interferon agonist in combination therapy for proliferative disorders [0012] The invention features a combination IFN therapy, having enhanced therapeutic activity, and useful in treating proliferative disorders, such as disease mediated by angiogenesis, cancer, and fibrotic disorders. In general, the method of the invention involves administering to an individual a Type II interferon receptor agonist and a Type I interferon receptor agonist concurrently, in an amount effective to ameliorate the clinical course of disease.

[0013] The invention features a method of treating a proliferative disorder, such as diseases mediated by angiogenesis, cancer, and fibrotic disorders, generally by providing a Type II interferon receptor agonist (e. g. IFN-gamma) and a Type I interferon receptor agonist (e. g.

IFN-alpha) concurrently, to an individual in amounts effective to reduce clinical symptoms of the disorder or to reduce morbidity or mortality in clinical outcomes. In one embodiment, pirfenidone or a pirfenidone analog is further co-administered. In further embodiments of the invention, the IFN receptor agonists are co-administered with other therapeutic agents, including antagonists of angiogenesis, anti-proliferative and/or cytotoxic agents, anti- inflammatory agents, anti-fibrotic agents, and the like. The invention also features a method of treating proliferative disorders by administering a Type II IFN receptor agonist and a Type I IFN receptor agonist in a synergistically effective amount to ameliorate the clinical cause of the disease.

[0014] In the method invention, the Type I interferon receptor agonist and Type II interferon- receptor agonist can be administered in the same formulation. Alternatively, they can be administered in separate formulations. When administered in separate formulations, administration can be substantially simultaneously or temporally spaced, for example, where the second agonist administered within about 24 hours of the first. The dual IFN receptor agonists may be administered subcutaneously in multiple doses, for example one to seven times per week, preferably about three times per week. Alternatively, the dual IFN receptor agonists can be administered by a controlled drug delivery device, for example providing the agonists to the individual in a substantially continuous manner, or in a desired pattern. The controlled drug delivery device can be an implantable infusion pump, for example, whereby the infusion pump delivers the agonists to the individual by subcutaneous infusion.

[0015] The administration of the Type I interferon receptor agonist and of the Type II interferon receptor agonist can be contemporaneous over the entire course of the treatment period, or can be administered over a period of time that is overlapping, such that initiation of treatment with one of the agonists precedes initiation of the other, and/or cessation of treatment with one of the agonists follows cessation of treatment with the other, and the like. In the context of the invention, "co-administration"and/or"co-treatment"includes administration of one agent to an individual during the course of treatment with another agent. Accordingly, the "combination"IFN receptor agonist therapy or"dual"IFN receptor agonist therapy of the invention is meant as the administration of a Type I IFN agonist (such as IFN-alpha) to an individual during the course of treatment with a Type II IFN agonist (such as IFN-gamma), and vice-versa.

[0016] In some embodiments, an additional therapeutic agent can be administered. For example, the combination IFN therapy can be augmented by co-administration of anti- angiogenic agents, such as antagonists of VEGF, bFGF, TGF-beta, or antagonists of the VEGF receptor (VEGF-R), bFGF receptor (bFGF-R), or TGF-beta receptor (TGF-P-R), for example, in the treatment of disease mediated by angiogenesis. Combination IFN receptor agonist therapy can be augmented by co-administration of anti-inflammatory agents such as antagonists of TNF, such as HUMIRATM (adalimumab, Abbott Laboratories) and antagonists of IL-1, for example IL-lRa (Arend et al., 2000, Arthritis Res. 2 (4): 245-248), in the treatment of fibrotic disorders or chronic inflammatory disorders. Combination IFN-therapy can be augmented by co-administration of anti-cancer agents, including anti-proliferative and/or cytotoxic agents, such as alkylating agents, anti-metabolites, metal-complexes (e. g. cisplatin and carboplatin), biological response modifiers (e. g. tyrosine kinase inhibitors), and the like, in the treatment of various cancers.

[0017] In some embodiments, any of the above-described methods may involve co- administration of IFN-alpha, which can be a consensus IFN-alpha (CIFN), together with IFN- gamma. In some embodiments, IFN-alpha (or CIFN) and IFN-gamma are administered together with an anti-proliferative agent, cytoxic drug, or biological response modifier.

[0018] An analgesic (e. g. acetaminophen, NSAIDs, ibuprofen, aspirin, and the like) can be administered for the avoidance or reduction of pain suffered by the individual that receives the combination interferon therapy. The additional agent may also be an antipsychotic agent (e. g. an SSRI, an anxiolytic, an anti-depressant, and the like) for the avoidance or reduction of any psychoses or any neuroses suffered by the individual that may be induced by the Type I interferon receptor agonist therapy and/or Type II interferon receptor agonist therapy.

[0019] A hematopoietic agent (e. g. erythropoietin, G-CSF, GM-CSF, thrombopoietin, and the like) can be administered for the avoidance or reduction of anemia (low red cell counts) or leukopenia (low white cell counts) that may be induced by the dual IFN therapy. Some of the above-described methods are useful as an adjuvant to known cancer therapies.

[0020] The Type I interferon receptor agonist may be, for example, an IFN-alpha, including a consensus interferon (CIFN). The Type II interferon receptor agonist may be, for example, an IFN-gamma. Thus the invention includes co-administering to a patient IFN-alpha or CIFN together with IFN-gamma.

[0021] The IFN-alpha molecules to be administered may be PEGylated IFN-a conjugates. The PEGylated IFN-a conjugate can be a monoPEGylated IFN-a, such as IFN-a polypeptide covalently linked to a single PEG moiety via a lysine residue or the N-terminal amino acid residue of the IFN-a polypeptide. In other embodiments, the monoPEGylated IFN-a conjugate is an IFN-a polypeptide covalently linked to a single PEG moiety via an amide bond between either the epsilon-amino group of a lysine residue or the alpha-amino group of the IFN-a polypeptide and an activated carboxyl group of the PEG moiety. In other embodiments, the monoPEGylated IFN-a conjugate is an IFN-a polypeptide covalently linked to a single, linear PEG moiety. In other embodiments, the monoPEGylated IFN-a conjugate is an IFN-a polypeptide covalently linked to a single, linear 30 kD PEG moiety. In other embodiments, the monoPEGylated IFN-a conjugate is an IFN-a polypeptide covalently linked to a single, linear 30 kD PEG moiety via an amide bond between the epsilon-amino group of a lysine residue or the alpha-amino group of the IFN-a polypeptide and an activated carboxyl group of the PEG moiety. In other embodiments, the monoPEGylated IFN-a conjugate is an IFN-a polypeptide covalently linked to a single, linear 30 kD PEG via an amide bond between the epsilon-amino group of a lysine residue or the alpha-amino group of the IFN-a polypeptide and an activated propionyl group of the PEG moiety. In other embodiments, the monoPEGylated IFN-a conjugate is an IFN-a polypeptide covalently linked to a single, linear monomethoxy-PEG (mPEG). In other embodiments, the monoPEGylated IFN-a conjugate is the product of a condensation reaction between an IFN-a polypeptide and a linear, succinimidyl propionate ester-activated 30 kD mPEG. In any of the foregoing methods using a PEGylated IFN-a conjugate, the IFN-a polypeptide can be a consensus interferon (CIFN) polypeptide. In any of the foregoing methods using a PEGylated IFN-a conjugate, the IFN-a polypeptide can be a CIFN polypeptide that is interferon alfacon-1.

Type II interferon agonist, SAPK inhibitor, and third therapeutic agent combination therapy for treating proliferative disorders [0022] In some embodiments, the invention features a combination therapy, having enhanced therapeutic activity, and useful in treating proliferative disorders, such as disease mediated by angiogenesis, cancer, and fibrotic disorders. In general, the method of the invention involves administering to an individual a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and at least a third therapeutic agent (e. g. , a palliative agent or an agent for the avoidance, treatment, or amelioration of a side effect of a therapeutic agent) concurrently, in an amount effective to ameliorate the clinical course of disease. In these embodiments, a SAPK inhibitor suitable for use specifically includes pirfenidone and pirfenidone analogs; and also specifically includes any compound of Formula I as set forth in U. S. Patent Publication No. 20030149041.

[0023] The invention features a method of treating a proliferative disorder, such as diseases mediated by angiogenesis, cancer, and fibrotic disorders, generally by administering to an individual in need thereof a first therapeutic agent that is a Type II interferon receptor agonist (e. g. IFN-gamma; IFN-y), a second therapeutic agent that is a SAPK inhibitor in combination therapy and in amounts effective to reduce clinical symptoms of the disorder or to reduce morbidity or mortality in clinical outcomes ; and a third therapeutic agent that is a palliative agent or an agent for the avoidance, treatment, or amelioration of a side effect of a therapeutic agent. In some embodiments, the SAPK inhibitor is a pirfenidone or a pirfenidone analog. In further embodiments of the invention, the above-mentioned first, second, and third therapeutic agents are co-administered with one or more other, additional therapeutic agents, which additional therapeutic agents include antagonists of angiogenesis, anti-proliferative and/or cytotoxic agents, anti-inflammatory agents, anti-fibrotic agents, and the like. The invention also features a method of treating proliferative disorders by administering a Type II IFN receptor agonist and a SAPK inhibitor in a synergistically effective amount, along with a third therapeutic agent (e.g., a palliative agent or an agent for the avoidance, treatment, or amelioration of a side effect of a therapeutic agent), to ameliorate the clinical cause of the disease.

[0024] In some embodiments, the Type II interferon receptor agonist and the SAPK inhibitor are administered in the same formulation. In other embodiments, the Type II interferon receptor agonist and the SAPK inhibitor are administered in separate formulations. When administered in separate formulations, administration can be substantially simultaneously or temporally spaced, for example, the second administered within about 24 hours of the first.

Generally, the third (palliative) agent is administered in a separate formulation from the first and second therapeutic agents. The first, second, and third therapeutic agents may be administered subcutaneously in multiple doses, for example one to seven times per week, preferably about three times per week. Alternatively, the first and/or second and/or third therapeutic agents can be administered by a controlled drug delivery device, for example providing the agonists to the individual in a substantially continuous manner, or in a desired pattern. The controlled drug delivery device can be an implantable infusion pump, for example, whereby the infusion pump delivers the agonists to the individual by subcutaneous infusion.

[0025] The administration of the Type II interferon receptor agonist and the SAPK inhibitor can be contemporaneous over the entire course of the treatment period, or can be administered over a period of time that is overlapping, such that initiation of treatment with the Type II interferon receptor agonist precedes initiation of the treatment with the SAPK inhibitor, and/or cessation of treatment with the Type II interferon receptor agonist follows cessation of treatment with the SAPK inhibitor, and the like. In the context of the invention,"co- administration"and/or"co-treatment"includes administration of one agent to an individual during the course of treatment with another agent. Accordingly, the"combination"therapy of the invention refers to the administration of a Type II IFN agonist (such as IFN-y) during the course of treatment with a SAPK inhibitor (such as pirfenidone or a pirfenidone analog), and vice-versa.

[0026] A subject method comprises administering a Type II interferon receptor agonist and a SAPK inhibitor in combined effective amounts; and a third therapeutic agent (e. g. , a palliative agent, or an agent for the avoidance, treatment, or amelioration of a side effect of a therapeutic agent). In some embodiments, the third therapeutic agent is a palliative agent. The palliative agent will in some embodiments be an analgesic (e. g. acetaminophen, a non-steroid anti- inflammatory drug (NSAID), ibuprofen,-aspirin, and the like). For example, an analgesic can be administered for the avoidance or reduction of pain suffered by the individual that receives the combination Type II interferon receptor agonist/SAPK inhibitor therapy. In other embodiments, the palliative agent is an antipsychotic agent (e. g. an SSRI, an anxiolytic, an anti-depressant, and the like) for the avoidance or reduction of any psychoses or any neuroses suffered by the individual that may be induced by one or more components of a subject combination therapy. In some embodiments, the palliative agent is an agent that ameliorates gastrointestinal discomfort such as nausea, diarrhea, gastrointestinal cramping, and the like.

[0027] In some embodiments, the third therapeutic agent is any agent that, when administered to the individual, avoids, treats, or ameliorates a side effect of a therapeutic agent administered in a subject combination therapy. In some embodiments, such an agent is a hematopoietic agent (e. g. erythropoietin, G-CSF, GM-CSF, thrombopoietin, and the like) which is administered for the avoidance, or reduction of anemia (low red cell counts) or leukopenia (low white cell counts) that may be induced by one or more components of a subject combination therapy.

[0028] In some embodiments, an additional therapeutic agent is administered. Other suitable additional therapeutic agents include antagonists of angiogenesis, anti-proliferative and/or cytotoxic agents, anti-inflammatory agents, anti-fibrotic agents, anti-neoplastic agents, anti-and the like.

[0029] In some embodiments, the additional therapeutic agent is an anti-angiogenic agent, an anti-inflammatory agent, a non-pirfenidone TNF-a antagonist, or an anti-cancer agent (e. g. , an anti-proliferative agent, a cytotoxic agent, an anti-neoplastic agent). A subject combination therapy can be augmented by co-administration of a non-pirfenidone antagonist of TNF-a, such as HUMIRATM (adalimumab, Abbott Laboratories), ENBRELS, REMICADES, and the like. A subject combination therapy can be augmented by co-administration of anti- inflammatory agents, in the treatment of fibrotic disorders or chronic inflammatory disorders.

A subject combination therapy can be augmented by co-administration of anti-cancer agents, including anti-proliferative and/or cytotoxic agents, such as alkylating agents, anti-metabolites, metal-complexes (e. g. cisplatin and carboplatin), biological response modifiers (e. g. tyrosine kinase inhibitors), and the like, in the treatment of various cancers.

Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat proliferative disorders [0030] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-is Actimmune (g) human IFN-ylb. In some embodiments, the VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR ("an anti-VEGFR ribozyme"), an antisense that inhibits a VEGFR ("an anti-VEGFR antisense"), and an siRNA that inhibits a VEGFR. Of particular interest in many embodiments is the treatment of humans.

[0031] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a Type II interferon receptor agonist, a VEGF antagonist, and a Type I interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN- a is INFERGEN consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 lcD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG- INTRONPEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYSSPEGylated IFN-a2a.

[0032] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a Type II interferon receptor agonist, a VEGF antagonist, and a tumor necrosis factor (TNF) antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the TNF antagonist is HUMIRA (g). In some embodiments, the TNF antagonist is ENBREL (g). In some embodiments, the TNF antagonist is REMICADE (g).

[0033] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a Type II interferon receptor agonist, a VEGF antagonist, and a stress activated protein kinase (SAPK) inhibitor in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

[0034] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a Type II interferon receptor agonist, a VEGF antagonist, a Type I interferon receptor agonist, and a TNF antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the TNF antagonist is HUMIRA (g). In some embodiments, the TNF antagonist is ENBRELS. In some embodiments, the TNF antagonist is REMICADE@.

[0035] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a Type II interferon receptor agonist, a VEGF antagonist, a Type I interferon receptor agonist, and a SAPK inhibitor in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

[0036] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a Type II interferon receptor agonist, a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the TNF antagonist is HUMIRAC.---In some embodiments, the TNF antagonist is ENBREL (g). In some embodiments, the TNF antagonist is REMICADE (g). In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

[0037] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an alkylating agent. In some embodiments, the alkylating agent is a nitrogen mustard. In other embodiments, the alkylating agent is an ethylenimine. In still other embodiments, the alkylating agent is an alkylsulfonate.

In additional embodiments, the alkylating agent is a triazene. In further embodiments, the allkylating agent is a nitrosourea.

[0038] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an antimetabolite. In some embodiments, the antimetabolite is a folic acid analog, such as methotrexate. In other embodiments, the antimetabolite is a purine analog, such as mercaptopurine, thioguanine and axathioprine. In still other embodiments, the antimetabolite is a pyrimidine analog, such as 5FU, UFT, capecitabine, gemcitabine and cytarabine.

[0039] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a vinca alkyloid. In some embodiments, the vinca alkaloid is a taxane, such as paclitaxel. In other embodiments, the vinca alkaloid is a podophyllotoxin, such as etoposide, teniposide, ironotecan, and topotecan.

[0040] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an antineoplastic antibiotic. In some embodiments, the antineoplastic antibiotic is doxorubicin.

[0041] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a platinum complex. In some embodiments, the platinum complex is cisplatin. In other embodiments, the platinum complex is carboplatin.

[0042] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a tyrosine kinase inhibitor other than a VEGFR tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor, such as type I receptor tyrosine kinase inhibitors (e. g. , inhibitors of epidermal growth factor receptors), type II receptor tyrosine kinase inhibitors (e. g. , inhibitors of insulin receptor), type III receptor tyrosine kinase inhibitors (e. g., inhibitors of platelet-derived growth factor receptor), and type IV receptor tyrosine kinase inhibitors (e. g. , fibroblast growth factor receptor). In other embodiments, the tyrosine kinase inhibitor is a non-receptor tyrosine kinase inhibitor, such as inhibitors of src kinases or janus kinases.

[0043] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of a receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is genistein. In other embodiments, the inhibitor is an epidermal growth factor receptor (EGFR) tyrosine kinase-specific antagonist, such as IRESSATM gefitinib, TARCEVATM erolotinib, or tyrphostin AG1478 (4- (3-chloroanilino)-6, 7-dimethoxyquinazoline. In still other embodiments, the inhibitor is any indolinone antagonist of Flk-1/KDR (VEGF-R2) tyrosine kinase activity. In further embodiments, the inhibitor is any of the substituted 3- [ (4, 5,6, 7- tetrahydro-lH-indol-2-yl) methylene]-1, 3-dihydroindol-2-one antagonists of Flk-1/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity. In additional embodiments, the inhibitor is any substituted 3- [ (3- or 4-carboxyethylpyrrol-2-yl) methylidenyl] indolin-2-one antagonist of Flt-1 (VEGF-R1), Flk-l/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity.

[0044] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of a non-receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is an antagonist of JAK2 tyrosine kinase activity, such as tyrphostin AG490 (2-cyano- 3- (3, 4-dihydroxyphenyl)-N- (benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of bcr-abl tyrosine kinase activity, such as GLEEVECTM imatinib mesylate.

[0045] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a serine/threonine kinase inhibitor.

In some embodiments, the serine/threonine kinase inhibitor is a receptor serine/threonine kinase inhibitor, such as antagonists of TGF- [3 receptor serine/threonine kinase activity. In other embodiments, the serine/threonine kinase inhibitor is a non-receptor serine/threonine kinase inhibitor, such as antagonists of the serine/threonine kinase activity of the MAP kinases, protein kinase C (PKC), protein kinase A (PKA), or the cyclin-dependent kinases (CDKs).

[0046] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of one or more kinases involved in cell cycle regulation. In some embodiments, the inhibitor is an antagonist of CDK2 activation, such as tryphostin AG490 (2-cyano-3- (3, 4-dihydroxyphenyl)-N- (benzyl)-2- propenamide). In other embodiments, the inhibitor is an antagonist of CDKl/cyclin B activity, such as alsterpaullone. In still other embodiments, the inhibitor is an antagonist of CDK2 kinase activity, such as indirubin-3'-monoxime.

[0047] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer; and co-administering to the patient an effective amounts of a taxane, and a platinum complex. In some embodiments, the taxane is paclitaxel and the platinum complex is cisplatin or carboplatin.

[0048] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer; and co-administering to the patient an effective amount of at least one additional antineoplastic drug that is a tumor-associated antigen antagonist, such as an antibody antagonist. In some embodiments involving the treatment of HER2-expressing tumors, the tumor-associated antigen antagonist is an anti-HER2 monoclonal antibody, such as HERCEPTINTM trastuzumab. In some embodiments involving the treatment of CD20- expressing tumors, such as B-cell lymphomas, the tumor-associated antigen antagonist is an anti-CD20 monoclonal antibody, such as RITUXANTM rituximab.

[0049] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts to treat the cancer; and co-administering to the patient an effective amount of at least one additional antineoplastic drug that is a tumor growth factor antagonist. In some embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor (EGF), such as an anti-EGF monoclonal antibody. In other embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor receptor erbB 1 (EGFR), such as an anti-EGFR monoclonal antibody antagonist of EGFR activation or signal transduction.

VEGF antagonist in combination therapy with a TNF antagonist or a SAPK inhibitor to treat proliferative disorders [0050] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a vascular endothelial growth factor (VEGF) antagonist and a tumor necrosis factor (TNF) antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR ("an anti-VEGFR ribozyme"), an antisense that inhibits a VEGFR ("an anti-VEGFR antisense"), and an siRNA that inhibits a VEGFR. In some embodiments, the TNF antagonist is HUMIRA (g). In some embodiments, the TNF antagonist is ENBRELO. In some embodiments, the TNF antagonist is REMICADE (Z. Of particular interest in many embodiments is the treatment of humans.

[0051] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist, a TNF antagonist, and a Type II interferon receptor agonist in combined effective-amounts to treat the proliferative disorder. In some embodiments, In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody-specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti- VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmunet) human IFN-ylb. In some embodiments, the TNF antagonist is HUMIRA@. In some embodiments, the TNF antagonist is ENBRELO. In some embodiments, the TNF antagonist is REMICADEC.

[0052] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGFantagonist, a TNF antagonist, and a Type I interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGENt consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a. In some embodiments, the IFN-a is PEG-INTRON (g) PEGylated IFN-a2b.

In some embodiments, the IFN-a is PEGASYSOPEGylated IFN-a2a. In some embodiments, the TNF antagonist is HUMIRA (g). In some embodiments, the TNF antagonist is ENBRELO.

In some embodiments, the TNF antagonist is REMICADE (».

[0053] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering à VEGF antagonist, a TNF antagonist, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGEN consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG- INTRONQ :) PEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYS#PEGylated IFN-a2a. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmuneg human IFN-ylb. In some embodiments, the TNF antagonist is HUMIRA). In some embodiments, the TNF antagonist is ENBREL (». In some embodiments, the TNF antagonist is REMICADEO.

[0054] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist and a stress activated protein kinase (SAPK) inhibitor in combined effective amounts to treat the proliferative disorder. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti- VEGFR antisense, and an siRNA that inhibits a VEGFR.

[0055] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist, a SAPK inhibitor, and a Type II interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti- VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune human IFN-ylb.

[0056] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist, a SAPK inhibitor, and a Type I interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti- VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGENS consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a. In some embodiments, the IFN-a is PEG-INTRONPEGylated IFN-a2b.

In some embodiments, the IFN-a is PEGASYS (3) PEGylated IFN-a2a.

[0057] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the SAPK inhibitors pirfenidone or a pirfenidone analog. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti- VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune (g) human IFN-ylb. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGEN consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG-INTRONPEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYS (g) PEGylated IFN-a2a.

[0058] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti- VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the TNF antagonist is HUMIRAS. In some embodiments, the TNF antagonist is ENBRELS. In some embodiments, the TNF antagonist is REMICADEO.

[0059] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and a Type II interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti- VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the TNF antagonist is HUMIRA@. In some embodiments, the TNF antagonist is ENBRELO. In some embodiments, the TNF antagonist is REMICADE (». In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune human IFN-ylb.

[0060] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and a Type I interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti- VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the TNF antagonist is HUMIRA (X3). In some embodiments, the TNF antagonist is ENBREL@D. In some embodiments, the TNF antagonist is REMICADE (S). In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN- a is INFERGEN (D consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG- INTRONPEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYSOPEGylated IFN-a2a.

[0061] The present invention features a method of treating a proliferative disorder (including cancer, a fibrotic disorder, an angiogenic disorder), the method generally involving administering a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the TNF antagonist is HUMIRAS. In some embodiments, the TNF antagonist is ENBRELS. In some embodiments, the TNF antagonist is REMICADE (E. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune human IFN-ylb. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGENO consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a. In some embodiments, the IFN-a is PEG-INTRON (MPEGylated IFN-a2b.

In some embodiments, the IFN-a is PEGASYSOPEGylated IFN-a2a.

[0062] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an alkylating agent. In some embodiments, the alkylating agent is-a nitrogen mustard. In other embodiments, the alkylating agent is an ethylenimine. In still other embodiments, the alkylating agent is an alkylsulfonate. In additional embodiments, the alkylating agent is a triazene. In further embodiments, the allkylating agent is a nitrosourea.

[0063] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an antimetabolite. In some embodiments, the antimetabolite is a folic acid analog, such as methotrexate. In other embodiments, the antimetabolite is a purine analog, such as mercaptopurine, thioguanine and axathioprine. In still other embodiments, the antimetabolite is a pyrimidine analog, such as 5FU, UFT, capecitabine, gemcitabine and cytarabine.

[0064] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a vinca alkyloid. In some embodiments, the vinca alkaloid is a taxane, such as paclitaxel. In other embodiments, the vinca alkaloid is a podophyllotoxin, such as etoposide, teniposide, ironotecan, and topotecan.

[0065] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an antineoplastic antibiotic. In some embodiments, the antineoplastic antibiotic is doxorubicin.

[0066] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a platinum complex. In some embodiments, the platinum complex is cisplatin. In other embodiments, the platinum complex is carboplatin.

[0067] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a tyrosine kinase inhibitor other than a VEGFR tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor, such as type I receptor tyrosine kinase inhibitors (e. g. , inhibitors of epidermal growth factor receptors), type II receptor tyrosine kinase inhibitors (e. g. , inhibitors of insulin receptor), type III receptor tyrosine kinase inhibitors (e. g. , inhibitors of platelet-derived growth factor receptor), and type IV receptor tyrosine kinase inhibitors (e. g. , fibroblast growth factor receptor). In other embodiments, the tyrosine kinase inhibitor is a non-receptor tyrosine kinase inhibitor, such as inhibitors of src kinases or janus kinases.

[0068] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of a receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is genistein. In other embodiments, the inhibitor is an epidermal growth factor receptor (EGFR) tyrosine kinase-specific antagonist, such as IRESSATM gefitinib, TARCEVATM erolotinib, or tyrphostin AG1478 (4- (3-chloroanilino)-6, 7- dimethoxyquinazoline. In still other embodiments, the inhibitor is any indolinone antagonist of Flk-1/KDR (VEGF-R2) tyrosine kinase activity. In further embodiments, the inhibitor is any of the substituted 3- [ (4, 56, 7-tetrahydro-1H-indol-2-yl) metliylene]-1, 3-dihydroindol-2-one antagonists of Flk-1/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity. In additional embodiments, the inhibitor is any substituted 3- [ (3- or 4-carboxyethylpyrrol-2-yl) methylidenyl] indolin-2-one antagonist of Flt-l (VEGF-R1), Flk-l/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity.

[0069] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of a non- receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is an antagonist of JAK2 tyrosine kinase activity, such as tyrphostin AG490 (2-cyano-3- (3, 4-dihydroxyphenyl)-N- (benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of bcr-abl tyrosine kinase activity, such as GLEEVECTMimatinib mesylate.

[0070] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer ; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is a serine/threonine kinase inhibitor. In some embodiments, the serine/threonine kinase inhibitor is a receptor serine/threonine kinase inhibitor, such as antagonists of TGF- [3 receptor serine/threonine kinase activity. In other embodiments, the serine/threonine kinase inhibitor is a non-receptor serine/threonine kinase inhibitor, such as antagonists of the serine/threonine kinase activity of the MAP kinases, protein kinase C (PKC), protein kinase A (PKA), or the cyclin-dependent kinases (CDKs).

[0071] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the cancer patient an effective amount of at least one additional antineoplastic drug that is an inhibitor of one or more kinases involved in cell cycle regulation. In some embodiments, the inhibitor is an antagonist of CDK2 activation, such as tryphostin AG490 (2-cyano-3- (3, 4-dihydroxyphenyl) - N- (benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of CDKl/cyclin B activity, such as alsterpaullone. In still other embodiments, the inhibitor is an antagonist of CDK2 kinase activity, such as indirubin-3'-monoxime.

[0072] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the patient an effective amounts of a taxane, and a platinum complex. In some embodiments, the taxane is paclitaxel and the platinum complex is cisplatin or carboplatin.

[0073] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the patient an effective amount of at least one additional antineoplastic drug that is a tumor-associated antigen antagonist, such as an antibody antagonist. In some embodiments involving the treatment of HER2-expressing tumors, the tumor-associated antigen antagonist is an anti-HER2 monoclonal antibody, such as HERCEPTINTMtrastuzumab. In'soine embodiments involving the treatment of CD20-expressing tumors, such as B-cell lymphomas, the tumor-associated antigen antagonist is an anti-CD20 monoclonal antibody, such as RITUXANTM rituximab.

[0074] In another aspect, the invention features a method of treating cancer by administering to a cancer patient a VEGF antagonist with a TNF antagonist and/or a SAPK inhibitor in combined effective amounts to treat the cancer; and co-administering to the patient an effective amount of at least one additional antineoplastic drug that is a tumor growth factor antagonist.

In some embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor (EGF), such as an anti-EGF monoclonal antibody. In other embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor receptor erbB 1 (EGFR), such as an anti-EGFR monoclonal antibody antagonist of EGFR activation or signal transduction.

[0075] In some embodiments, a subject combination therapy further comprises administering one or more additional therapeutic agents. In some embodiments, a subject combination therapy further comprises administering a side effect management agent.

Type II interferon receptor agonist and TGF-ß antagonist in combination therapy to treat fibrotic disorders [0076] The invention features a method of treating fibrosis, generally involving administering to an individual (i) a Type II interferon receptor agonist and (ii) TGF-ß antagonist concurrently, in an amount effective to ameliorate the clinical course of the disease, e. g., reducing the disease burden, slowing the progression of the disease, or reducing morbidity or mortality in the clinical outcome of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF- (3 antagonist is GleevecTM.

[0077] In one aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-ß antagonist, and pirfenidone or a pirfenidone analog in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-Y. In some embodiments, the TGF-P antagonist is GleevecTM.

[0078] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-ß antagonist, and a third agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-ß antagonist is GleevecTM. In some embodiments, the TNF antagonist is selected from etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor (where suitable SAPK inhibitors include pirfenidone and pirfenidone analogs; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No. 20030149041).

[0079] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- ß antagonist and an endothelin receptor antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-ß antagonist is GleevecTM. In some embodiments, the endothelin receptor agonist is Tracleejm.

[0080] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-ß antagonist, and a Type I or III interferon receptor agonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-ß antagonist is GleevecTM. In some of these embodiments, the Type I interferon receptor agonist is IFN-a. In some of these embodiments, the IFN-a is a pegylated IFN-a, such as monoPEG (30 kD, linear) -ylated consensus IFN-a, PEGASYS peginterferon alfa-2a, or PEG-lNTRON (g) peginterferon alfa-2b. In other embodiments, the IFN-a is an unpegylated IFN-a, such as INFERGENS interferon alfacon-1, ROFERONO interferon alfa-2a, or INTRO-AS interferon alfa-2b.

[0081] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-ß antagonist, pirfenidone or a pirfenidone analog, and a fourth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-P antagonist is GleevecTM. In some embodiments, the TNF-antagonist is selected from etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0082] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- p antagonist, pirfenidone or a pirfenidone analog, and a fourth agent that is an endothelin receptor antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-Y. In some embodiments, the TGF-ß antagonist is GleevecTM. In some embodiments, the endothelin receptor agonist is Tracleer.

[0083] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-ß antagonist, pirfenidone or a pirfenidone analog, and a Type I or III interferon receptor agonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-Y. In some embodiments, the TGF-ß antagonist is GleevecTM. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some of these embodiments, the IFN-a is a pegylated IFN-a, such as monoPEG (30 kD, linear) -ylated consensus IFN-a, PEGASYSX peginterferon alfa-2a, or PEG-INTRON peginterferon alfa-2b. In other embodiments, the IFN-a is an unpegylated IFN-a, such as INFERGENS interferon alfacon-1, ROFERON interferon alfa-2a, or INTRO-A interferon alfa-2b.

[0084] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- ß antagonist, an endothelin receptor antagonist, and a fourth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-ß antagonist is GleevecTM. In some embodiments, the endothelin receptor agonist is Tracleefrm. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0085] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-ß antagonist, a Type I or III interferon receptor agonist, and a fourth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF- (3 antagonist is GleevecTM. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some of these embodiments, the IFN-a is a pegylated IFN-a, such as monoPEG (30 kD, linear)-ylated consensus IFN-a, PEGASYSO peginterferon alfa-2a, or PEG-INTRON peginterferon alfa-2b. In other embodiments, the IFN-a is an unpegylated IFN-a, such as INFERGEND interferon alfacon-1, ROFERON interferon alfa-2a, or INTRO-AS interferon alfa-2b. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0086] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF- (3 antagonist, an endothelin receptor antagonist, and a Type I or III interferon receptor agonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-ß antagonist is GleevecTM. In some embodiments, the endothelin receptor antagonist is Tracleefrm. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some of these embodiments, the IFN-a is a pegylated IFN-a, such as monoPEG (30 lcD, linear) - ylated consensus IFN-a, PEGASYS peginterferon alfa-2a, or PEG-INTRO peginterferon alfa-2b. In other embodiments, the IFN-a is an unpegylated IFN-a, such as INFERGEN interferon alfacon-1, ROFERON interferon alfa-2a, or INTRO-AU interferon alfa-2b.

[0087] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- (3 antagonist, an endothelin receptor antagonist, pirfenidone or a pirfenidone analog, and a fifth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-P antagonist is GleevecTM. In some embodiments, the endothelin receptor agonist is Tracleer. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0088] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- ß antagonist, a Type I or III interferon receptor agonist, pirfenidone or a pirfenidone analog, and a fifth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-ß antagonist is Gleevec. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some of these embodiments, the IFN-a is a pegylated IFN-a, such as monoPEG (30 kD, linear) -ylated consensus IFN-a, PEGASYSS peginterferon alfa-2a, or PEG-INTRON (S) peginterferon alfa-2b. In other embodiments, the IFN-a is an unpegylated IFN-a, such as INFERGENO interferon alfacon-1, ROFERONO interferon alfa-2a, or INTRO-A interferon alfa-2b. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0089] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- ß antagonist, a Type I or III interferon receptor agonist, an endothelin receptor antagonist, and a fifth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y.

In some embodiments, the TGF- (3 antagonist is GleevecTM. In some embodiments, the endothelin receptor agonist is Tracleer. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some of these embodiments, the IFN-a is a pegylated IFN-a, such as monoPEG (30 kD, linear) -ylated consensus IFN-a, PEGASYS peginterferon alfa-2a, or PEG-INTRON peginterferon alfa-2b. In other embodiments, the IFN-a is an unpegylated IFN-a, such as INFERGEN interferon alfacon-l, ROFERON (» interferon alfa-2a, or INTRON-A interferon alfa-2b. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0090] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- antagonist, a Type I or III interferon receptor agonist, an endothelin receptor antagonist, and pirfenidone or a pirfenidone analog, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y.

In some embodiments, the TGF-ß antagonist is GleevecTM. In some embodiments, the endothelin receptor agonist is Tracleer. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some of these embodiments, the IFN-a is a pegylated IFN-a, such as monoPEG (30 kD, linear) -ylated consensus IFN-a, PEGASYS peginterferon alfa-2a, or PEG-INTRON peginterferon alfa-2b. In other embodiments, the IFN-a is an unpegylated IFN-a, such as INFERGEN) interferon alfacon-1, ROFERONS interferon alfa-2a, or INTRO-AS interferon alfa-2b.

[0091] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- P antagonist, a Type I or III interferon receptor agonist, an endothelin receptor antagonist, pirfenidone or a pirfenidone analog, and a sixth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the TGF-ß antagonist is GleevecTM. In some embodiments, the endothelin receptor agonist is Tracleer. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some of these embodiments, the IFN-a is a pegylated IFN-a, such as monoPEG (30 kD, linear) -ylated consensus IFN-a, PEGASYS peginterferon alfa-2a, or PEG-INTRON peginterferon alfa-2b. In other embodiments, the IFN-a is an unpegylated IFN-a, such as INFERGEN interferon alfacon-1, ROFERON interferon alfa-2a, or INTRO-AS interferon alfa-2b. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS [0092] Figure 1 depicts various downstream signaling events that are triggered by TNF binding to a TNF receptor.

[0093] Figure 2 depicts the effect of pirfenidone on the enzymatic activity of c Jun kinases (JNK).

[0094] Figure 3 depicts the effect of pirfenidone on the enzymatic activity of various cyclin dependent kinases (CDK).

[0095] Figure 4 depicts the effect of pirfenidone on the enzymatic activity of various stress- activated protein kinases.

[0096] Figure 5 depicts the effect of pirfenidone on the enzymatic activity of various SRC protein kinases.

[0097] Figure 6 depicts results showing that pirfenidone does not affect IFN-y-induced STAT1 tyrosine phosphorylation.

[0098] Figure 7 depicts results indicating that pirfenidone ("Pir") binding to SAPK3 (p3 8y) is competitive with ATP binding.

[0099] Figure 8 depicts results indicating that SAPK3 Ki can be determined from ATP/pirfenidone competitive binding data.

[00100] Figure 9 depicts results indicating that pirfenidone can only bind SAPK3 after the phosphorylation substrate associates with the enzyme.

DEFINITIONS [00101] The terms"individual,""host,""subject,"and"patient"are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.

[00102] As used herein, the terms"treatment,""treating,"and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment, "as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i. e. , arresting its development; and (c) relieving the disease, i. e. , causing regression of the disease.

[00103] As used herein, the term"a Type I interferon receptor agonist"refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds to and causes signal transduction via the receptor. Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[00104] As used herein, the term"a Type II interferon receptor agonist"refers to any naturally- occurring or non-naturally-occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[00105] As used herein, the term"a Type III interferon receptor agonist"refers to any naturally occurring or non-naturally occurring ligand of human IL-28 receptor a ("IL-28R"), the amino acid sequence of which is described by Sheppard, et al. , infra. , that binds to and causes signal transduction via the receptor.

[00106] As used herein, "a SAPK inhibitor"refers to any agent that inhibits kinase activity of SAPK2a, and/or SAPK2b, and/or SAPK3. Generally, the agent is less than about 10 kD, less than about 5 kD, less than about 3 kD, less than about 2.5 kD, or less than about 1 kD. In some embodiments, a SAPK inhibitor is a non-proteinaceous compound. In some embodiments, the term"SAPK inhibitor"includes pirfenidone and pirfenidone analogs; and also includes a compound of Formula I as set forth in U. S. Patent Publication No. 20030149041. In some embodiments, the term"SAPK inhibitor"excludes pirfenidone and pirfenidone analogs; and also excludes a compound of Formula I as set forth in U. S. Patent Publication No.

20030149041.

[00107] As used herein, the term"pirfenidone"means 5-methyl-1-phenyl-2-(lH)-pyridone.

[00108] As used herein, the term"pirfenidone analog"means any compound of Formula I, IIA or IIB below.

[00109] As used herein, the term"specific pirfenidone analog"and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1.

[00110] The terms"non-pirfenidone TNF-a antagonist, ""non-pirfenidone TNF antagonist"are used interchangeably herein and include agents that decrease the level of TNF-a synthesis, agents that block or inhibit the binding of TNF-a to a TNF-a receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction, which agents are other for pirfenidone or a pirfenidone analog. Tumor necrosis factor (TNF) antagonists include, but are not limited, such as anti-TNF antibodies (e. g. REMICADETM anti-TNF monoclonal antibody) and soluble TNF receptor (e. g. ENBRELTM TNF receptor-Ig immunoadhesin), and HUMIRA@.

[00111] As used herein, the term"vascular endothelial growth factor antagonist,"or"VEGF antagonist"refers to any agent that antagonizes an effect of VEGF, including an agent that blocks the binding of VEGF to a VEGF receptor (e. g., VEGF-R1 or VEGF-R2), an agent that inhibits the transduction of a signal mediated by a VEGF receptor, e. g. , a signal that is mediated by binding of a ligand or other VEGF receptor binding agent to a VEGF receptor.

[00112] As used herein, the tenn"TGF- (3 antagonist"refers to any agent that decreases the level of TGF-ß synthesis, any agent that blocks or inhibits the binding of TGF- (3 to a TGF-P receptor, and any agent that blocks or inhibits TGF-p receptor-mediated signal transduction.

Unless otherwise expressly stated, every reference to a"TGF-ß antagonist"herein will be understood to mean a TGF-ß antagonist other than pirfenidone or a pirfenidone analog.

[00113] As used herein, the term"endothelin receptor antagonist"refers to any agent blocks or inhibits the binding of endothelin to an endothelin receptor, and any agent that blocks or inhibits endothelin receptor-mediated signal transduction.

[00114] The term"chemotherapeutic"agent, drug or compound (or"chemotherapy", in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (i. e. , non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM) ; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin ; a sarcodictyin ; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e. g. calicheamicin, especially calicheamicin gammalI and calicheamicin phill, see, e. g. , Agnew, Chem. Intl. Ed. Engl., 33 : 183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin ; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubincin (Adramycinw) (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C,-mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine ; demecolcine; diaziquone; elfornithine ; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea ; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone ; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine ; PST@ ; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2', 2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mamiomustine ; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; taxoids, e. g. paclitaxel (TAXOL (t, Bristol Meyers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTEREC, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (GemzarTM) ; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum ; etoposide (VP-16); ifosfamide ; mitroxantrone ; vancristine; vinorelbine (NavelbineTM) ; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda ; ibandronate ; CPT-11; topoisomerase inhibitor RFS 2000; difluromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in the definition of"chemotherapeutic agent"are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Farestonw) ; inhibitors of the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4 (5)-imidazoles, aminoglutethimide, megestrol acetate (Megace), exemestane, formestane, fadrozole, vorozole (Rivisor), letrozole (Femara), and anastrozole (ArimidexTM) ; and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin ; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[00115] The term"antineoplastic"agent, drug or compound is meant to refer to any agent, including any chemotherapeutic agent, biological response modifier (including without limitation (i) proteinaceous, i. e. peptidic, molecules capable of elaborating or altering biological responses and (ii) non-proteinaceous, i. e. non-peptidic, molecules capable of elaborating or altering biological responses), cytotoxic agent, or cytostatic agent, that reduces proliferation of a neoplastic cell.

[00116] The term"anti-inflammatory"agent, drug or compound is meant to include agents prevent or reduce inflammation and include, for example, tumor necrosis factor (TNF) antagonists, such as anti-TNF antibodies (e. g. REMICADETM anti-TNF monoclonal antibody) and soluble TNF receptor (e. g. ENBRELTM TNF receptor-Ig immunoadhesin), and IL-1 antagonists, such as IL-lRa.

[00117] The term"anti-fibrotic"agent, drug or compound is meant to encompass agents that prevent or reduce fibrosis, including: Type II interferon receptor agonists (e. g. interferon- gamma); pirfenidone and pirfenidone analogs; anti-angiogenic agents, such as VEGF antagonists, VEGF receptor antagonists, bFGF antagonists, bFGF receptor antagonists, TGF- beta antagonists, and TGF-beta receptor antagonists; and anti-inflammatory agents, including tumor necrosis factor (TNF) antagonists, such as anti-TNF antibodies (e. g. REMICADETManti- TNF monoclonal antibody) and soluble TNF receptor (e. g. ENBRELTMTNF receptor-Ig immunoadhesin), and IL-1 antagonists, such as IL-lRa.

[00118] The terms"angiogenic agent,""angiogenic compound, "and"angiogenic factor"are meant to include agents that promote neovascularization, such as VEGF, bFGF, and TGF-beta.

[00119] The terms"anti-angiogenic"or"angiostatic"agent, drug or compound, or "angiogenesis inhibitor, "are meant to include agents that prevent or reduce neovascularization, such as VEGF antagonists, VEGF receptor antagonists, bFGF antagonists, bFGF receptor antagonists, TGF-beta antagonists, and TGF-beta receptor antagonists.

[00120] The term"biological response modifier"refers to any proteinaceous (i. e. , peptidic) molecule or any non-proteinaceous (i. e., non-peptidic) molecule capable of elaborating or altering a biological response relevant to the treatment of cancer. Examples of biological response modifiers include antagonists of tumor-associated antigens, such as anti-tumor antigen antibodies, antagonists of cellular receptors capable of inducing cell proliferation, agonists of cellular receptors capable of inducing apoptosis, such as Apo-2 ligands, Type I interferon receptor agonists, such as interferon-alpha molecules and interferon-beta molecules, Type II interferon receptor agonists, such as interferon-gamma molecules, growth factor cytokines, such as hematopoietic cytokines, including erythropoietins, such as EPOGENTM epoetin-alfa, granulocyte colony stimulating factors (G-CSFs), such as NEUPOGENTM filgrastim, granulocyte-macrophage colony stimulating factors (GM-CSFs), and thrombopoietins, lymphocyte growth factor cytokines, such as interleukin-2, and antagonists of growth factor cytokines, including EGF inhibitors, EGF receptor inhibitors, such as ERBITUXTM cetuximab (anti-VEGF receptor monoclonal antibody), IRESSATM gefitinib and TARCEVATM erolotinib, and antagonists of angiogenic factors, e. g. vascular endothelial cell growth factor (VEGF) antagonists, such as AVASTINTM bevacizumab (anti-VEGF monoclonal antibody).

[00121] The term"therapeutically effective amount"is meant an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent, effective to facilitate a desired therapeutic effect.

The precise desired therapeutic effect will vary according to the condition to be treated, the formulation to be administered, and a variety of other factors that are appreciated by those of ordinary skill in the art.

[00122] A"fibrotic condition, ""fibroproliferative condition, ""fibrotic disease," "fibroproliferative disease, ""fibrotic disorder, "and"fibroproliferative disorder"are used interchangeably to refer to a condition, disease or disorder that is characterized by dysregulated proliferation or activity of fibroblasts and/or pathologic or excessive accumulation of collagenous tissue. Typically, any such disease, disorder or condition is amenable to treatment by administration of a compound having anti-fibrotic activity. Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology, liver fibrosis, and renal fibrosis. Other exemplary fibrotic conditions include musculoskeletal fibrosis, cardiac fibrosis, post-surgical adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

[00123] As used herein, the term"hepatic fibrosis, "used interchangeably herein with"liver fibrosis, "refers to the growth of scar tissue in the liver that can occur, e. g. , in the context of a chronic hepatitis infection.

[00124] As used herein, the term"liver function"refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e. g. , albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y- glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[00125] The term"angiogenesis-mediated disease, ""angiogenesis-mediated disorder," "angiogenic disease,"and"angiogenic disorder"are used interchangeably to refer to any disease characterized by pathological neovascularization, including all solid tumors, rheumatoid arthritis, psoriasis, atherosclerosis, diabetic and other retinopathies, retrolental fibroplasia, age-related macular degeneration, neovascular glaucoma, hemangiomas, thyroid hyperplasias (including Grave's disease), an inflammatory bowel disease such as, for example, Crohn's disease or ulcerative colitis, and corneal transplantation.

[00126] The term"proliferative disorder"and"proliferative disease"are used interchangeably to refer to any disease or condition characterized by pathological cell growth or proliferation, including all fibroproliferative or fibrotic conditions, angiogenesis-mediated diseases, neoplastic disorders, and chronic inflammatory disorders mediated by dysregulated or unrestrained cellular proliferation.

[00127] The terms"cancer,""neoplasm,"and"tumor"are used interchangeably herein to refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. Cancerous cells can be benign or malignant.

[00128] The term"dosing event"as used herein refers to administration of a therapeutic agent to a patient in need thereof, which event may encompass one or more releases of agent from a drug dispensing device.

[00129]"Continuous delivery"as used herein (e. g. , in the context of"continuous delivery of a substance to a tissue") is meant to refer to movement of drug to a delivery site, e. g. , into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.

[00130] "Controlled release"as used herein (e. g., in the context of"controlled drug release") is meant to encompass release of substance (e. g., a Type I interferon receptor agonist, e. g. , IFN- a; e. g. , a Type II interferon receptor agonist, e. g., IFN-y) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use.

"Controlled release"thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e. g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).

[00131] "Patterned"or"temporal"as used in the context of drug delivery means delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e. g. , other than a period associated with, for example a bolus injection)."Patterned"or "temporal"drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e. g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.

[00132] The term"controlled drug delivery device"is meant to encompass any device wherein the release (e. g. , rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.

[00133] By"substantially continuous"as used in, for example, the context of"substantially continuous infusion"or"substantially continuous delivery"is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero. Furthermore, "substantially continuous"drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e. g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.

[00134] By"substantially steady state"as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUCghr average) The AUCghr average is defined as the quotient (q) of the area under the curve of the biological parameter over the entirety of the time course (AUCtotal) divided by the number of 8 hour intervals in the time course (ttotalll3days) i. e. , q = (AUctotal)/ (ttotall/3days)-For example, in the context of a serum concentration of a drug, the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum concentration of the drug over time for any 8 hour period during the time course (AUCghr) is no more than about 20% above or about 20% below the average area under the curve of serum concentration of the drug over an 8 hour period in the time course (AUCghr average), i. e., the AUC8hr is no more than 20% above or 20% below the AUCghr average for the serum concentration of the drug over the time course.

[00135] As used herein, any compound or agent described as"effective for the avoidance or amelioration of side effects induced by a Type I interferon receptor agonist and/or a Type II interferon receptor agonist, "or as"effective for reducing or eliminating the severity or occurrence of side effects induced by a Type I interferon receptor agonist and/or a Type II interferon receptor agonist, "or any compound or agent described by language with a meaning similar or equivalent to that of either of the foregoing quoted passages, is/are defined as a compound (s) or agent (s) that when co-administered to a patient in an effective amount along with a given dosing regimen of Type I interferon receptor agonist and Type II interferon receptor agonist combination therapy, abates or eliminates the severity or occurrence of side effects experienced by a patient in response to the given dosing regimen of the interferon receptor agonist combination therapy, as compared to the severity or occurrence of side effects that would have been experienced by the patient in response to the same dosing regimen of the interferon receptor agonist combination therapy without co-administration of the agent.

[00136] In many embodiments, the effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are synergistic amounts. As used herein, a "synergistic combination"or a"synergistic amount"of a Type II interferon receptor agonist and a Type I interferon receptor agonist is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a proliferative disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type II interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the Type I interferon receptor agonist when administered at the same dosage as a monotherapy.

[00137] In some embodiments of the invention, a selected amount of a Type II interferon receptor agonist and a selected amount of a Type I interferon receptor agonist are effective when used in combination therapy for a disease, but the selected amount of the Type II interferon receptor agonist and/or the selected amount of the Type I interferon receptor agonist is ineffective when used in monotherapy for the disease. Thus, the invention encompasses (1) regimens in which a selected amount of a Type I interferon receptor agonist enhances the therapeutic benefit of a selected amount of a Type II interferon receptor agonist when used in combination therapy for a disease, where the selected amount of the Type I interferon receptor agonist provides no therapeutic benefit when used in monotherapy for the disease (2) regimens in which a selected amount of a Type II interferon receptor agonist enhances the therapeutic benefit of a selected amount of a Type I interferon receptor agonist when used in combination therapy for a disease, where the selected amount of the Type II interferon receptor agonist provides no therapeutic benefit when used in monotherapy for the disease and (3) regimens in which a selected amount of a Type II interferon receptor agonist and a selected amount of a Type I interferon receptor agonist provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the Type II interferon receptor agonist and the Type I interferon receptor agonist, respectively, provides no therapeutic benefit when used in monotherapy for the disease. As used herein, a"synergistically effective amount"or"synergistically effective combination''of a Type II interferon receptor agonist and a Type I interferon receptor agonist, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (1)- (3) above.

[00138] As used herein, any compound or agent described as"effective for the avoidance or amelioration of side effects induced by a SAPK inhibitor, "or as"effective for reducing or eliminating the severity or occurrence of side effects induced by a SAPK inhibitor,"or any compound or agent described by language with a meaning similar or equivalent to that of either of the foregoing quoted passages, is/are defined as a compound (s) or agent (s) that when co-administered to a patient in an effective amount along with a given dosing regimen of a subject SAPK inhibitor combination therapy, abates or eliminates the severity or occurrence of side effects experienced by a patient in response to the given dosing regimen of the subject combination therapy, as compared to the severity or occurrence of side effects that would have been experienced by the patient in response to the same dosing regimen of the subject therapy without co-administration of the agent.

[00139] As used herein, any compound or agent described as"effective for the avoidance or amelioration of side effects induced by a therapeutic agent, "or as"effective for reducing or eliminating the severity or occurrence of side effects induced by a therapeutic agent, "or any compound or agent described by language with a meaning similar or equivalent to that of either of the foregoing quoted passages, is/are defined as a compound (s) or agent (s) that when co-administered to a patient in an effective amount along with a given dosing regimen of a subject combination therapy that comprises administering the therapeutic agent, abates or eliminates the severity or occurrence of side effects experienced by a patient in response to the given dosing regimen of the subject combination therapy that comprises administering the therapeutic agent, as compared to the severity or occurrence of side effects that would have been experienced by the patient in response to the same dosing regimen of the subject therapy without co-administration of the agent.

[00140] In many embodiments, the effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are synergistic amounts. As used herein, a"synergistic combination"or a"synergistic amount"of a Type II interferon receptor agonist and a SAPK inhibitor is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a proliferative disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type II interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the SAPK inhibitor when administered at the same dosage as a monotherapy.

[00141] In many embodiments, the effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are synergistic amounts. As used herein, a"synergistic combination''or a"synergistic amount"of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist, is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a proliferative disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type II interferon receptor agonist when administered at that same dosage as a monotherapy (ii) the therapeutic or prophylactic benefit of the Type I or III interferon receptor agonist when administered at the same dosage as a monotherapy and (iii) the therapeutic or prophylactic benefit of the TNF-a antagonist when administered at the same dosage as a . monotherapy.

[00142] In some embodiments of the invention, a selected amount of a Type II interferon receptor agonist, a selected amount of a Type I or III interferon receptor agonist, and a selected amount of a TNF-a antagonist are effective when used in triple therapy for a disease, but the selected amount of the Type II interferon receptor agonist, the selected amount of the Type I or III interferon receptor agonist, or the selected amount of the TNF-a antagonist is ineffective when used in monotherapy for the disease, or combination (s) of any two of the foregoing drugs are ineffective when used in double therapy for the disease.

[00143] Thus, the invention encompasses: (1) regimens in which a selected amount of a Type I or III interferon receptor agonist enhances the therapeutic benefit of a selected amount of (i) a Type II interferon receptor agonist and (ii) a TNF-a antagonist, when used in triple therapy for a disease, where the selected amount of the Type I or III interferon receptor agonist provides no therapeutic benefit when used in monotherapy for the disease; (2) regimens in which a selected amount of a Type II interferon receptor agonist enhances the therapeutic benefit of a selected amount of (i) a Type I or III interferon receptor agonist and (ii) a TNF-a antagonist, when used in triple therapy for a disease, where the selected amount of the Type II interferon receptor agonist provides no therapeutic benefit when used in monotherapy for the disease ; (3) regimens in which a selected amount of a TNF-a antagonist enhances the therapeutic benefit of (i) a selected amount of a Type II interferon receptor agonist and (ii) a Type I or III interferon receptor agonist, when used in triple therapy for a disease, where the selected amount of the TNF-a antagonist provides no therapeutic benefit when used in monotherapy for the disease; (4) regimens in which a selected amount of (i) a Type II interferon receptor agonist and (ii) a TNF-a antagonist enhances the therapeutic benefit of a selected amount of a Type I or III interferon receptor agonist, when used in triple therapy for a disease, where the selected amount of the Type II interferon receptor agonist and TNF-a antagonist provides no therapeutic benefit when used in double therapy for the disease; (5) regimens in which a selected amount of (i) a Type I or III interferon receptor agonist and (ii) a TNF-a antagonist enhances the therapeutic benefit of a selected amount of a Type II interferon receptor agonist, when used in triple therapy for a disease, where the selected amount of the Type I or III interferon receptor agonist and TNF-a antagonist provides no therapeutic benefit when used in double therapy for the disease; (6) regimens in which a selected amount of (i) a Type II interferon receptor agonist and (ii) a Type I or III interferon receptor agonist enhances the therapeutic benefit of a selected amount of a TNF-a antagonist, when used in triple therapy for a disease, where the selected amount of the Type II interferon receptor agonist and Type I or III interferon receptor agonist provides no therapeutic benefit when used in double therapy for the disease; and (7) regimens in which a selected amount of a Type I or III interferon receptor agonist, a selected amount of a Type II interferon receptor agonist, and a selected amount of a TNF-a antagonist provide a therapeutic benefit when used in triple therapy for a disease, where each of the selected amounts of the Type II interferon receptor agonist, the Type I or III interferon receptor agonist, and the TNF-a antagonist, respectively, provides no therapeutic benefit when used in monotherapy for the disease.

[00144] As used herein, a"synergistically effective amount"or"synergistically effective combination"of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (1)-(7) above.

[00145] In many embodiments, the effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist, are synergistic amounts. As used herein, a"synergistic combination" or a"synergistic amount"of a Type II interferon receptor agonist and a TNF-a antagonist, is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a fibrotic disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type II interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the TNF-a antagonist when administered at the same dosage as a monotherapy.

[00146] In some embodiments of the invention, a selected amount of a Type II interferon receptor agonist and a selected amount of a TNF-a antagonist are effective when used in triple therapy for a disease, but either drug is ineffective when used in monotherapy for the disease.

[00147] Thus, the invention encompasses: (1) regimens in which a selected amount of a Type II interferon receptor agonist enhances the therapeutic benefit of a selected amount of a TNF-a antagonist when used in double therapy for a disease, where the selected amount of the Type II interferon receptor agonist provides no therapeutic benefit when used in monotherapy for the disease; (2) regimens in which a selected amount of a TNF-a antagonist enhances the therapeutic benefit of a selected amount of a Type II interferon receptor agonist when used in double therapy for a disease, where the selected amount of the TNF-a antagonist provides no therapeutic benefit when used in monotherapy for the disease; and (3) regimens in which a selected amount of a Type II interferon receptor agonist and a selected amount of a TNF-a antagonist provide a therapeutic benefit when used in double therapy for a disease, where each of the selected amounts of the Type II interferon receptor agonist and the TNF-a antagonist, respectively, provides no therapeutic benefit when used in monotherapy for the disease.

[00148] As used herein, a"synergistically effective amount"or"synergistically effective combination"of a Type II interferon receptor agonist and a TNF-a antagonist, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (1)- (3) above.

[00149] In many embodiments, the effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist, are synergistic amounts. As used herein, a"synergistic combination" or a"synergistic amount"of pirfenidone or a pirfenidone analog and a TNF-a antagonist, is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a proliferative disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the pirfenidone or a pirfenidone analog when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the TNF-a antagonist when administered at the same dosage as a monotherapy.

[00150] In some embodiments of the invention, a selected amount of pirfenidone or a pirfenidone analog, and a selected amount of a TNF-a antagonist are effective when used in triple therapy for a disease, but the selected amount of the pirfenidone or a pirfenidone analog, or the selected amount of the TNF-a antagonist is ineffective when used in monotherapy for the disease, or combination (s) of any two of the foregoing drugs are ineffective when used in double therapy for the disease.

[00151] Thus, the invention encompasses: (1) regimens in which a selected amount of pirfenidone or a pirfenidone analog enhances the therapeutic benefit of a selected amount of a TNF-a antagonist, when used in combination therapy for a disease, where the selected amount of the TNF-a antagonist provides no therapeutic benefit when used in monotherapy for the disease; (2) regimens in which a selected amount of a TNF-a antagonist enhances the therapeutic benefit of a selected amount of pirfenidone or a pirfenidone analog when used in combination therapy for a disease, where the selected amount of pirfenidone or pirfenidone analog provides no therapeutic benefit when used in monotherapy for the disease; (3) regimens in which a selected amount of pirfenidone or a pirfenidone analog enhances the therapeutic benefit of a selected amount of a TNF-a antagonist, when used in combination therapy for a disease, where the selected amount of the pirfenidone or pirfenidone analog provides no therapeutic benefit when used in monotherapy for the disease; and (4) regimens in which a selected amount of a TNF-a antagonist enhances the therapeutic benefit of a selected amount of pirfenidone or a pirfenidone analog when used in combination therapy for a disease, where the selected amount of TNF-a antagonist provides no therapeutic benefit when used in monotherapy for the disease.

[00152] As used herein, a"synergistically effective amount"or"synergistically effective combination"of pirfenidone or a pirfenidone analog, and a TNF-a antagonist, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (1)- (4) above.

[00153] In many embodiments, the effective amounts of a Type II interferon receptor agonist, and TGF-ß antagonist, are synergistic amounts. As used herein, a"synergistic combination"or a"synergistic amount"of a Type II interferon receptor agonist and a TGF- (3 antagonist, is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a fibrotic disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type II interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the TGF-ß antagonist when administered at the same dosage as a monotherapy.

[00154] In some embodiments of the invention, a selected amount of a Type II interferon receptor agonist, and a selected amount of a TGF-ß antagonist are effective when used in combination therapy for a fibrotic disease, but the selected amount of the Type II interferon receptor agonist, or the selected amount of TGF- (3 antagonist is ineffective when used in monotherapy for the disease.

[00155] Thus, the invention encompasses: (1) regimens in which a selected amount of a Type II interferon receptor agonist enhances the therapeutic benefit of a selected amount of TGF-P antagonist, when used in combination therapy for a disease, where the selected amount of the Type II interferon receptor agonist provides no therapeutic benefit when used in monotherapy for the disease; (2) regimens in which a selected amount of TGF-ß antagonist enhances the therapeutic benefit of a selected amount of a Type II interferon receptor agonist when used in combination therapy for a disease, where the selected amount of the TGF- (3 antagonist provides no therapeutic benefit when used in monotherapy for the disease; and (3) regimens in which a selected amount of TGF-/3 antagonist and a selected amount of a Type II interferon receptor agonist provide a therapeutic benefit when used in combination therapy for a disease, where the selected amounts of TGF-P antagonist and Type II interferon receptor agonist, respectively, provide no therapeutic benefit when used in monotherapy for the disease.

[00156] As used herein, a"synergistically effective amount"or"synergistically effective combination"of a Type II interferon receptor agonist, and a TGF- (3 antagonist, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (1)- (3) above.

[00157] In many embodiments, the effective amounts of a Type II interferon receptor agonist, and NAC, are synergistic amounts. As used herein, a"synergistic combination"or a "synergistic amount"of a Type II interferon receptor agonist and NAC, is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a fibrotic disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type II interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of NAC when administered at the same dosage as a monotherapy.

[00158] In some embodiments of the invention, a selected amount of a Type II interferon receptor agonist, and a selected amount of NAC are effective when used in combination therapy for a fibrotic disease, but the selected amount of the Type II interferon receptor agonist, or the selected amount of NAC is ineffective when used in monotherapy for the disease.

[00159] Thus, the invention encompasses: (1) regimens in which a selected amount of a Type II interferon receptor agonist enhances the therapeutic benefit of a selected amount of NAC, when used in combination therapy for a disease, where the selected amount of the Type II interferon receptor agonist provides no therapeutic benefit when used in monotherapy for the disease; (2) regimens in which a selected amount of NAC enhances the therapeutic benefit of a selected amount of a Type II interferon receptor agonist when used in combination therapy for a disease, where the selected amount of NAC provides no therapeutic benefit when used in monotherapy for the disease; and (3) regimens in which a selected amount of NAC and a selected amount of a Type II interferon receptor agonist provide a therapeutic benefit when used in combination therapy for a disease, where the selected amounts of NAC and Type II interferon receptor agonist, respectively, provide no therapeutic benefit when used in monotherapy for the disease.

[00160] As used herein, a"synergistically effective amount"or"synergistically effective combination"of a Type II interferon receptor agonist and NAC, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (1)- (3) above.

[00161] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[00162] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[00163] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one. of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[00164] It must be noted that as used herein and in the appended claims, the singular forms"a", "and", and"the"include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to"a dose"includes a plurality of such doses and reference to"the method''includes reference to one or more methods and equivalents thereof known to those skilled in the art, and so forth.

[00165] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

DETAILED DESCRIPTION OF THE INVENTION [00166] The present invention provides methods of treating proliferative disorders, including angiogenesis-mediated disorders, cancer, and fibrotic disorders. In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor. The present invention further provides methods of treating fibrotic disorders. In some embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist; and a tumor necrosis factor (TNF) antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-ß) antagonist. In other, embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat proliferative disorders [00167] The inventor has surprisingly discovered that enhanced Type II interferon receptor agonist activity, including enhanced IFN-gamma activity, can be obtained in the treatment of a proliferation disorder by co-administering to a patient a Type II interferon receptor agonist, such as IFN-gamma, together with a Type I interferon receptor agonist, such as IFN-alpha. In alternative embodiments of the invention, this enhanced"dual IFN receptor agonist"therapy further includes administering additional therapeutic agents, including antagonists of angiogenesis, anti-proliferative and/or cytotoxic agents, anti-inflammatory agents, anti-fibrotic agents, and the like. In one embodiment, pirfenidone or a pirfenidone analog is co- administered with the dual IFN receptor agonist therapy.

[00168] In some embodiments, the dual IFN receptor agonist therapy of the present invention provides a synergistic effect that is useful for treating proliferative disorders, including angiogenesis-mediated diseases, various cancers, and fibrotic disorders. Specifically, the invention provides for the enhanced activity of a Type II interferon receptor agonist, such as IFN-gamma, when co-administered with a Type I interferon receptor agonist, such as IFN- alpha, in the treatment of proliferative disorders. In one embodiment, additional agents such as pirfenidone or pirfenidine analog, or other agents effective for treatment of angiogenesis- mediated disease, fibrotic disease, or cancer, are co-administered with the IFN receptor agonists. The dual IFN receptor agonist therapy is useful in the treatment of proliferative disorders that may or may not respond to a Type II interferon receptor agonist alone, and provides enhanced response to IFN-gamma alone, for example, in the treatment of diseases mediated by angiogenesis, cancer, and fibrotic disorders.

2) Type II interferon receptor agonist, SAPK inhibitor, and third therapeutic agent in combination therapy for treating proliferative disorders [00169] In some embodiments, the present invention provides methods for treating a proliferative disorder, including angiogenesis-mediated disorders, cancer, and fibrotic disorders, the methods generally involving administering to an individual in need thereof an effective amount of first therapeutic agent, wherein the first therapeutic agent is a Type II interferon receptor agonist, an effective amount of a second therapeutic agent, wherein the second therapeutic agent is a stress-activated protein kinase (SAPK) inhibitor, wherein the combined amounts of the first and second therapeutic agents are effective to treat the disorder; and administering an effective amount of a third therapeutic agent, e. g. , a palliative agent or an agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent (e. g. , a first therapeutic agent, a second therapeutic agent, or an additional therapeutic agent). In these embodiments, suitable SAPK inhibitors include pirfenidone and pirfenidone analogs; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No.

20030149041.

[00170] The methods of the invention provide for the co-administration of an effective amount of a third therapeutic agent, e. g. , a palliative agent or other therapeutic agent that reduces the severity or occurrence of side effects frequently experienced by individuals as a result of treatment with the SAPK inhibitor and/or the Type II interferon receptor agonist.

[00171] Side effects of Type II interferon receptor agonist treatment include, but are not limited to, fever, malaise, tachycardia, chills, headache, arthralgia, myalgia, myelosuppression, suicide ideation, platelet suppression, neutropenia, lymphocytopenia, erythrocytopenia (anemia), and anorexia. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a Type II interferon receptor agonist by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the SAPK inhibitor/Type II interferon receptor agonist combination therapy is administered without the palliative agent. For example, if a fever is experienced with the SAPK inhibitor/Type II interferon receptor agonist combination therapy, then the body temperature of an individual treated with the Type II interferon receptor agonist combination therapy and palliative agent according to the instant invention is reduced by at least 0.5 degree Fahrenheit, and in some embodiments is within the normal range, e. g. , at or near 98. 6 °F.

[00172] Side effects of SAPK inhibitor treatment (e. g. , treatment with pirfenidone or a pirfenidone analog) include gastrointestinal disturbances and discomfort. Gastrointestinal disturbances include nausea, diarrhea, gastrointestinal cramping, and the like. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a SAPK inhibitor (e. g. , pirfenidone or a pirfenidone analog) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the SAPK inhibitor/Type II interferon receptor agonist combination therapy is administered without the palliative agent.

[00173] Side effects of other, additional therapeutic agents (e. g. , anti-angiogenic agents; anti- cancer agents such as anti-proliferative agents, anti-neoplastic agents, and cytotoxic agents; anti-fibrotic agents; non-pirfenidone TNF-a antagonists; and anti-inflammatory agents) are well known. For example, side effects of anti-neoplastic agents include gastrointestinal discomfort. Other side effects of additional therapeutic agents include fever, malaise, etc.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat proliferative disorders [00174] In some embodiments, the present invention provides methods for treating a proliferative disorder, including angiogenesis-mediated disorders, cancer, and fibrotic disorders, the methods generally involving administering to an individual in need thereof an effective amount of a Type II interferon receptor agonist and an effective amount of a vascular endothelial growth factor (VEGF) antagonist to treat the disorder. In some embodiments, the method further involves administering an effective amount of a Type I interferon receptor agonist. In some embodiments, the method further involves administering an effective amount of a TNF antagonist. In other embodiments, the method further involves administering an effective amount of a stress activated protein kinase (SAPK) inhibitor (where suitable SAPK inhibitors include pirfenidone and pirfenidone analogs; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No. 20030149041). In other embodiments, the method further involves administering two or more of a TNF antagonist, a SAPK inhibitor, and a Type I interferon receptor agonist. Additional therapeutic agents that may be administered in a subject combination therapy include an anti-cancer agent (e. g. , an anti-proliferative agent, an anti-neoplastic agent, a cytotoxic agent, etc. ), an anti-fibrotic agent, and an agent for the reduction or avoidance of a side effect of a therapeutic agent. In some embodiments, a subject combination therapy further includes administration of a side effect management agent.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat proliferative disorders [00175] In some embodiments, the present invention provides methods for treating a proliferative disorder, including angiogenesis-mediated disorders, cancer, and fibrotic disorders, the methods generally involving administering to an individual in need thereof a vascular endothelial growth factor (VEGF) antagonist and a tumor necrosis factor (TNF) antagonist or a stress activated protein kinase (SAPK) inhibitor in combined effective amounts to treat the disorder. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00176] In some embodiments, a subject combination therapy involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat a proliferative disorder. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00177] Additional therapeutic agents that may be administered in a subject combination therapy include an anti-cancer agent (e. g. , an anti-proliferative agent, an anti-neoplastic agent, a cytotoxic agent, etc. ), an anti-fibrotic agent, and an agent for the reduction or avoidance of a side effect of a therapeutic agent. In some embodiments, a subject combination therapy further includes administration of a side effect management agent.

5) Type I or Type III interferon receptor agonist, Type II interferon receptor agonist, and TNF antagonist in combination therapy to treat fibrotic disorders [00178] In some embodiments, the present invention provides methods for treating a fibrotic disorder in an individual having a fibrotic disorder. Of particular interest in many embodiments is treatment of humans.

[00179] The method generally involves administering an effective amount of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist, and TNF-a antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

6) Type II interferon receptor agonist and TNF antagonist in combination therapy to treat fibrotic disorders [00180] In some embodiments, the present invention provides methods for treating a fibrotic disorder in an individual having a fibrotic disorder. Of particular interest in many embodiments is treatment of humans.

[00181] The method generally involves administering an effective amount of a Type II interferon receptor agonist and an effective amount of a TNF-a antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

7) Pirfenidone and TNF antagonist in combination therapy to treat fibrotic disorders [00182] In some embodiments, the present invention provides methods for treating a fibrotic disorder in an individual having a fibrotic disorder. Of particular interest in many embodiments is treatment of humans.

[00183] The method generally involves administering an effective amount of pirfenidone or a pirfenidone analog and TNF-a antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

8) Type II interferon receptor agonist and TGF-ß antagonist in combination therapy to treat fibrotic disorders [00184] In some embodiments, the present invention provides methods for treating a fibrotic disorder in an individual having a fibrotic disorder. Of particular interest in many embodiments is treatment of humans.

[00185] The method generally involves administering an effective amount of a Type II interferon receptor agonist and a TGF-ß antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis.

The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

9) SAPK inhibitors in monotherapy and combination therapy for the treatment of fibrotic disorders [00186] In some embodiments, the present invention provides methods for treating a fibrotic disorder in an individual having a fibrotic disorder, involving administering a SAPK inhibitor in monotherapy or in combination therapy. Of particular interest in many embodiments is treatment of humans.

[00187] In these embodiments, the method generally involves administering an effective amount of an agent that inhibits a stress-activated protein kinase (SAPK), otherwise referred to herein as"a SAPK inhibitor,"e. g. , the agent inhibits enzymatic activity of a SAPK, where the SAPK inhibitor is other than pirfenidone or a pirfenidone analog, and where the SAPK inhibitor is other than a compound of Formula I as set forth in U. S. Patent Publication No.

20030149041. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

10) N-acetyl cysteine and SAPK inhibitor in combination therapy for treating fibrotic disorders [00188] In some embodiments, the present invention provides methods for treating a-fibrotic disorder in an individual having a fibrotic disorder. Of particular interest in many embodiments is treatment of humans.

[00189] The method generally involves administering an effective combination of N- acetylcytsteine (NAC) and an agent that inhibits a stress-activated protein kinase (SAPK), otherwise referred to herein as"a SAPK inhibitor. "The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis.

The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

[00190] Without being limited to any particular mechanism of action, it is believed that NAC and SAPK inhibitor combination therapy will provide additive or synergistic down modulation of inflammatory processes that contribute to the pathogenesis of fibrotic disorders. SAPK is an important mediator of TNFR signal transduction. Thus, a SAPK inhibitor is expected to downregulate TNF activation of inflammatory processes involved in the etiology of fibrotic disease. As a scavenger of free radicals, NAC is expected to reduce the destruction of tissue caused by non-specific immune cell activity at disease sites. In addition, NAC can inhibit free radical-mediated activation of NF-KB, a potent inducer of TNF-a. Therefore, NAC is expected to reduce blood levels of TNF and TNF-mediated inflammation. Since NAC and SAPK inhibitor intervene at different stages of the inflammatory cascade, it is believed that combination therapy with these agents will achieve an additive or synergistic improvement in clinical outcome compared to monotherapy with either agent in the treatment of fibrotic disorders.

11) N-acetyl cysteine and Type II interferon receptor agonist in combination therapy for treating fibrotic disorders [00191] In some embodiments, the present invention provides methods for treating a fibrotic disorder in an individual having a fibrotic disorder. Of particular interest in many embodiments is treatment of humans.

[00192] The method generally involves administering an effective amount of a Type II interferon receptor agonist and N-acetylcysteine (NAC). The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis.

The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

[00193] Without being limited to any particular mechanism of action, it is believed that NAC and Type 11 interferon receptor agonist combination therapy will provide additive or synergistic benefit in the treatment of fibrotic disorders. As demonstrated below, IFN-y is an anti-fibrotic agent that downregulates TGF-p-induced collagen deposition. Thus, IFN-y is expected to inhibit or curtail the dysregulated collagen production involved in the etiology of fibrotic disease. However, IFN-y is also a potent activator of non-specific immune cells that can contribute to inflammation at disease sites. The pro-inflammatory activity of IFN-y could augment the inflammatory processes involved in the etiology of fibrotic disease, thereby limiting the effectiveness of IFN-y in the treatment of fibrotic disorders.

[00194] As a scavenger of free radicals, NAC is expected to reduce the destruction of tissue caused by non-specific immune cell activity at disease sites. It is believed that the anti- inflammatory activity of NAC can offset or mitigate any inflammation induced by exogenously administered IFN-y, thereby increasing the therapeutic index of IFN-y in the treatment of fibrotic disorders. In addition, NAC can inhibit free radical-mediated activation of NF-XB, a potent inducer of TNF-a. Therefore, NAC is expected to reduce blood levels of TNF and TNF-mediated inflammation. Since NAC and IFN-y act on different processes in the pathogenesis of fibrotic disorders, and since NAC has the potential to increase the therapeutic index of IFN-y, it is believed that combination therapy with these agents will achieve an additive or synergistic improvement in clinical outcome compared to monotherapy with either agent in the treatment of fibrotic disorders TREATMENT METHODS [00195] The present invention provides methods of treating proliferative disorders, including angiogenesis-mediated disorders, cancer, and fibrotic disorders. In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor. The present invention further provides methods of treating fibrotic disorders. In some embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist; and a tumor necrosis factor (TNF) antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-ß) antagonist. In other embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist.

PROLIFERATIVE DISORDERS [00196] The present invention provides methods of treating proliferative disorders, including angiogenesis-mediated disorders, cancer, and fibrotic disorders. In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat proliferative disorders [00197] In some embodiments, the methods of the present invention generally involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist concurrently. For convenience, treatments involving administering a Type II interferon receptor agonist and a Type I interferon receptor agonist are collectively referred to herein as "interferon receptor agonist therapy, ""interferon receptor agonist treatment,""combination IFN receptor agonist therapy, "or"dual IFN receptor agonist therapy." 2) Type II interferon receptor agonist, SAPK inhibitor, and third therapeutic agent in combination therapy for treating proliferative disorders [00198] In some embodiments, the present invention provides methods for treatment of proliferative disorders. In some embodiments, the present invention provides methods for treatment of cancer. In other embodiments, present invention provides methods for treatment of a fibrotic disorder. In other embodiments, present invention provides methods for treatment of an angiogenic disorder. In these embodiments, the methods generally involve administering to an individual in need thereof an effective amount of a Type II interferon receptor agonist, and an effective amount of a SAPK inhibitor (where suitable SAPK inhibitors include pirfenidone and pirfenidone analogs ; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No. 20030149041), and a third therapeutic agent (e. g. , a palliative agent or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent). In some embodiments, the methods further involve administering an effective amount of an additional therapeutic agent (e. g. , at least a fourth therapeutic agent), which additional therapeutic agent may be an anti-cancer agent (e. g. , an anti-neoplastic agent, an anti-proliferative agent, a cytotoxic agent), an anti-angiogenic agent, an anti-inflammatory agent, an anti-fibrotic agent, or a non-pirfenidone TNFa antagonist.

3) Type 11 interferon receptor agonist and VEGF antagonist in combination therapy to treat proliferative disorders [00199] The present invention provides methods for treating a proliferative disorder, including angiogenesis-mediated disorders, cancer, and fibrotic disorders, the methods generally involving administering to an individual in need thereof an effective amount of a Type II interferon receptor agonist and an effective amount of a vascular endothelial growth factor (VEGF) antagonist to treat the disorder.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat proliferative disorders [00200] In some embodiments, the present invention provides methods for treating a proliferative disorder, including angiogenesis-mediated disorders, cancer, and fibrotic disorders, the methods generally involving administering to an individual in need thereof a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, in combined effective amounts to treat the disorder. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00201] In some embodiments, a subject combination therapy involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat a proliferative disorder. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

CANCER THERAPY [00202] The present invention provides a method of treating cancer, the method generally involving administering to an individual in need thereof a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, in combined effective amounts to treat the cancer. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00203] In some embodiments, a subject combination therapy to treat cancer involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the cancer. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-Y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00204] In some embodiments, the methods are effective to reduce the growth rate of a tumor by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of growth of the tumor, when compared to a-suitable control. In some of these embodiments, "effective amounts"of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are amounts that are sufficient to reduce tumor growth rate by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of tumor growth, when compared to a suitable control. In an experimental animal system, a suitable control may be a genetically identical animal not treated with the VEGF antagonist and the TNF antagonist, or the VEGF antagonist and the SAPK inhibitor. In non-experimental systems, a suitable control may be the tumor load present before administering the VEGF antagonist and the TNF antagonist, or the VEGF antagonist and the SAPK inhibitor. Other suitable controls may be a placebo control.

[00205] Whether growth of a tumor is inhibited can be determined using any known method, including, but not limited to, a proliferation assay; a 3H-thymidine uptake assay; and the like.

[00206] The methods are useful for treating a wide variety of cancers, including carcinomas, sarcomas, leukemias, and lymphomas.

[00207] Carcinomas that can be treated using a subject method include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), bladder carcinoma, including transitional cell carcinoma (a malignant neoplasm of the bladder), bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, renal cell carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelieal carcinoma, and nasopharyngeal carcinoma, etc.

[00208] Sarcomas that can be treated using a subject method include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[00209] Other solid tumors that can be treated using a subject method include, but are not limited to, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.

[00210] Leukemias that can be treated using a subject method include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias (neoplastic transformation of a multipotential hematopoietic stem cell or a hematopoietic cell of restricted lineage potential; c) chronic lymphocytic leukemias (CLL; clonal proliferation of immunologically immature and functionally incompetent small lymphocytes), including B-cell CLL, T-cell CLL prolymphocytic leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts). Lymphomas that can be treated using a subject method include, but are not limited to, B-cell lymphomas (e. g. , Burkitt's lymphom) ; Hodgkin's lymphoma; and the like.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat cancer [00211] In some embodiments, a subject method of treating cancer comprises administering effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist. The methods are effective to reduce a tumor load by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total eradication of the tumor, when compared to a suitable control. Thus, in these embodiments, "effective amounts"of a Type II interferon receptor agonist and a Type I interferon receptor agonist are amounts of the Type II interferon receptor agonist and the Type I interferon receptor agonist that are sufficient to reduce tumor load by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total eradication of the tumor, when compared to a suitable control. In an experimental animal system, a suitable control may be the tumor load present in a genetically identical animal not treated with the Type II interferon receptor agonist and Type I interferon receptor agonist combination therapy. In non-experimental systems, a suitable control may be the tumor load present before administering the Type II interferon receptor agonist and Type I interferon receptor agonist combination therapy. Other suitable controls may be a placebo control.

[00212] Whether a tumor load has been decreased can be determined using any known method, including, but not limited to, measuring solid tumor mass; counting the number of tumor cells using cytological assays; fluorescence-activated cell sorting (e. g. , using antibody specific for a tumor-associated antigen) to determine the number of cells bearing a given tumor antigen; computed tomography scanning, magnetic resonance imaging, and/or x-ray imaging of the tumor to estimate and/or monitor tumor size; measuring the amount of tumor-associated antigen in a biological sample, e. g. , blood; and the like.

[00213] The methods are effective to reduce the growth rate of a tumor by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of growth of the tumor, when compared to a suitable control. Thus, in these embodiments, "effective amounts"of a Type II interferon receptor agonist and a Type I interferon receptor agonist are amounts of the Type II interferon receptor agonist and the Type I interferon receptor agonist that are sufficient to reduce tumor growth rate by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of tumor growth, when compared to a suitable control. In an experimental animal system, a suitable control may be the growth rate of a tumor in a genetically identical animal not treated with the Type II interferon receptor agonist and Type I interferon receptor agonist combination therapy. In non-experimental systems, a suitable control may be the growth rate of a tumor observed before administering the Type II interferon receptor agonist and Type I interferon receptor agonist combination therapy. Other suitable controls may be a placebo control.

[00214] Whether growth of a tumor is inhibited can be determined using any known method, including, but not limited to, an in vitro proliferation assay such as a 3H-thymidine uptake assay, and the like.

2) Type II interferon receptor agonist, SAPK inhibitor, and third therapeutic agent in combination therapy for treating cancer [00215] In some embodiments, a subject method of treating cancer in an individual having a cancer comprises administering to an individual in need thereof a therapeutically effective amount of a Type II interferon receptor agonist, a therapeutically effective amount of a SAPK inhibitor (where suitable SAPK inhibitors include pirfenidone and pirfenidone analogs; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No.

20030149041, and a third therapeutic agent (e. g. , a palliative agent or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent).

[00216] The methods are effective to reduce a tumor load by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total eradication of the tumor, when compared to a suitable control. Thus, in these embodiments,"effective amounts"of a Type II interferon receptor agonist and a SAPK inhibitor are amounts of the Type II interferon receptor agonist and the SAPK inhibitor that are sufficient to reduce tumor load by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total eradication of the tumor, when compared to a suitable control. In an experimental animal system, a suitable control may be the tumor load present in a genetically identical animal not treated with the Type II interferon receptor agonist and SAPK inhibitor combination therapy. In non-experimental systems, a suitable control may be the tumor load present before administering the Type II interferon receptor agonist and SAPK inhibitor combination therapy. Other suitable controls may be a placebo control.

[00217] Whether a tumor load has been decreased can be determined using any known method, including, but not limited to, measuring solid tumor mass; counting the number of tumor cells using cytological assays; fluorescence-activated cell sorting (e. g. , using antibody specific for a tumor-associated antigen) to determine the number of cells bearing a given tumor antigen; computed tomography scanning, magnetic resonance imaging, and/or x-ray imaging of the tumor to estimate and/or monitor tumor size; measuring the amount of tumor-associated antigen in a biological sample, e. g. , blood; and the like.

[00218] The methods are effective to reduce the growth rate of a tumor by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of growth of the tumor, when compared to a suitable control. Thus, in these embodiments, "effective amounts"of a Type II interferon receptor agonist and a SAPK inhibitor are amounts of the Type II interferon receptor agonist and the SAPK inhibitor that are sufficient to reduce tumor growth rate by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of tumor growth, when compared to a suitable control. In an experimental animal system, a suitable control may be the growth rate of a tumor in a genetically identical animal not treated with the Type II interferon receptor agonist and SAPK inhibitor combination therapy. In non-experimental systems, a suitable control may be the growth rate of a tumor observed before administering the Type II interferon receptor agonist and SAPK inhibitor combination therapy. Other suitable controls may be a placebo control.

[00219] Whether growth of a tumor is inhibited can be determined using any known method, including, but not limited to, an in vitro proliferation assay such as a 3H-thymidine uptake assay, and the like.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat cancers [00220] In some embodiments, the present invention provides a method of treating a cancer, the method generally involving administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist in combined effective amounts to treat the cancer. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-is Actimmune (t human IFN-ylb. In some embodiments, the VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR.

Of particular interest in many embodiments is the treatment of humans. In some embodiments, a subject method further comprises administering one or more of a Type I interferon receptor agonist, a TNF antagonist, and a SAPK inhibitor.

[00221] The methods are effective to reduce the growth rate of a tumor by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of growth of the tumor, when compared to a suitable control. Thus, in these embodiments, "effective amounts"of a Type II interferon receptor agonist and a VEGF antagonist are sufficient to reduce tumor growth rate by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of tumor growth, when compared to a suitable control. In an experimental animal system, a suitable control may be a genetically identical animal not treated with the Type II interferon receptor agonist and the VEGF antagonist. In non-experimental systems, a suitable control may be the tumor load present before administering the Type II interferon receptor agonist and the VEGF antagonist. Other suitable controls may be a placebo control.

[00222] Whether growth of a tumor is inhibited can be determined using any known method, including, but not limited to, a proliferation assay as described in the Example; a 3H-thymidine uptake assay ; and the like.

[00223] In many embodiments, the effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are synergistic amounts. As used herein, a"synergistic combination" or a"synergistic amount"of a Type II interferon receptor agonist and a VEGF antagonist is a combined dosage that is more effective in the therapeutic or prophylactic treatment of cancer than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type II interferon receptor agonist when administered at the same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit the VEGF antagonist when administered at that same dosage as a monotherapy.

[00224] In some embodiments, a subject combination therapy for treating cancer comprises administering a Type II interferon receptor agonist, a VEGF antagonist, and a Type I interferon receptor agonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN- a is INFERGEN consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG- INTRON (g) PEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYS O PEGylated IFN-a2a.

[00225] In some embodiments, a subject combination therapy for treating cancer comprises administering a Type II interferon receptor agonist, a VEGF antagonist, and a tumor necrosis factor (TNF) antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the TNF antagonist is HUMIRAC. In some embodiments, the TNF antagonist is ENBRELS. In some embodiments, the TNF antagonist is REMICADEO.

[00226] In some embodiments, a subject combination therapy for treating cancer comprises administering a Type II interferon receptor agonist, a VEGF antagonist, and a stress activated protein kinase (SAPK) inhibitor in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

[00227] In some embodiments, a subject combination therapy for treating cancer comprises administering a Type II interferon receptor agonist, a VEGF antagonist, a Type I interferon receptor agonist, and a TNF antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the TNF antagonist is HUMIRA. In some embodiments, the TNF antagonist is ENBRELO. In some embodiments, the TNF antagonist is REMICADE (R).

[00228] In some embodiments, a subject combination therapy for treating cancer comprises administering a Type II interferon receptor agonist, a VEGF antagonist, a Type I interferon receptor agonist, and a SAPK inhibitor in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

[00229] In some embodiments, a subject combination therapy for treating cancer comprises administering a Type II interferon receptor agonist, a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. In some embodiments, the TNF antagonist is HUMIRAS. In some embodiments, the TNF antagonist is ENBRELO. In some embodiments, the TNF antagonist is REMICADEiE). In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

[00230] In some embodiments, a subject combination therapy for treating cancer is administered to a patient as an adjuvant to a standard cancer therapy.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat cancer [00231] In some embodiments, the present invention provides a method of treating cancer, the method generally involving administering to an individual in need thereof a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor (where suitable SAPK inhibitors include pirfenidone and pirfenidone analogs ; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No. 20030149041), in combined effective amounts to treat the cancer. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00232] In some embodiments, a subject combination therapy to treat cancer involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the cancer. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00233] The methods are effective to reduce the growth rate of a tumor by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of growth of the tumor, when compared to a suitable control. Thus, in these embodiments, "effective amounts"of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are amounts that are sufficient to reduce tumor growth rate by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 85%, or at least about 90%, up to total inhibition of tumor growth, when compared to a suitable control.

In an experimental animal system, a suitable control may be a genetically identical animal not treated with the VEGF antagonist and the TNF antagonist, or the VEGF antagonist and the SAPK inhibitor, . In non-experimental systems, a suitable control may be the tumor load present before administering the VEGF antagonist and the TNF antagonist, or the VEGF antagonist and the SAPK inhibitor, . Other suitable controls may be a placebo control.

[00234] Whether growth of a tumor is inhibited can be determined using any known method, including, but not limited to, a proliferation assay as described in the Example ; a 3H-thymidine uptake assay ; and the like.

[00235] In many embodiments, the effective amounts of a VEGF antagonist and a TNF antagonist are synergistic amounts. As used herein, a"synergistic combination"or a "synergistic amount"of a VEGF antagonist and a TNF antagonist is a combined dosage that is more effective in the therapeutic or prophylactic treatment of cancer than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the VEGF antagonist when administered at the same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit the TNF antagonist when administered at that same dosage as a monotherapy.

[00236] In many embodiments, the effective amounts of a VEGF antagonist and a SAPK inhibitor are synergistic amounts. As used herein, a"synergistic combination"or a "synergistic amount"of a VEGF antagonist and a SAPK inhibitor is a combined dosage that is more effective in the therapeutic or prophylactic treatment of cancer than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the VEGF antagonist when administered at the same dosage as-a monotherapy and (ii) the therapeutic or prophylactic benefit the SAPK inhibitor when administered at that same dosage as a monotherapy.

[00237] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist and a TNF antagonist in combined effective amounts to treat the cancer. The VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the TNF antagonist is HUMIRA (». In some embodiments, the TNF antagonist is ENBREL (». In some embodiments, the TNF antagonist is REMICADEO. Of particular interest in many embodiments is the treatment of humans.

[00238] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a TNF antagonist, and a Type II interferon receptor agonist in combined effective amounts to treat the cancer. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-is Actimmune (g) human IFN-ylb. In some embodiments, the TNF antagonist is HUMIRAS. In some embodiments, the TNF antagonist is ENBRELS. In some embodiments, the TNF antagonist is REMICADE#.

[00239] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGFantagonist, a TNF antagonist, and a Type I interferon receptor agonist in combined effective amounts to treat the cancer. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN- a is INFERGEN consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG- INTRON#PEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYS (g) PEGylated IFN-a2a. In some embodiments, the TNF antagonist is HUMIRA (R). In some embodiments, the TNF antagonist is ENBRELS. In some embodiments, the TNF antagonist is REMICADE).

[00240] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a TNF antagonist, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts to treat the cancer. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGENO consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 lcD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG-INTRONOPEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYS#PEGylated IFN-a2a. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is ActimmunetE) human IFN-ylb.

In some embodiments, the TNF antagonist is HUMIRA (t. In some embodiments, the TNF antagonist is ENBREL (g). In some embodiments, the TNF antagonist is REMICADE (g).

[00241] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist and a stress activated protein kinase (SAPK) inhibitor in combined effective amounts to treat the cancer. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR.

[00242] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a SAPK inhibitor, and a Type II interferon receptor agonist in combined effective amounts to treat the cancer. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune (g) human IFN-ylb.

[00243] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a SAPK inhibitor, and a Type I interferon receptor agonist in combined effective amounts to treat the cancer. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN- a is INFERGENC consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG- INTRON (g) PEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYS (» PEGylated IFN-a2a.

[00244] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts to treat the cancer. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune human IFN-ylb. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGEN (g consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a. In some embodiments, the IFN-a is PEG-INTRON (» PEGylated IFN-a2b.

In some embodiments, the IFN-a is PEGASYS (» PEGylated IFN-a2a.

[00245] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in combined effective amounts to treat the cancer. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the TNF antagonist is HUMIRAS. In some embodiments, the TNF antagonist is ENBRELO. In some embodiments, the TNF antagonist is REMICADEO.

[00246] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and a Type II interferon receptor agonist in combined effective amounts to treat the cancer. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the TNF antagonist is HUMIRA@. In some embodiments, the TNF antagonist is ENBREL (T. In some embodiments, the TNF antagonist is REMICADE (g).

In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmuneæ human IFN-ylb.

[00247] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and a Type I interferon receptor agonist in combined effective amounts to treat the cancer. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the TNF antagonist is HUMIRA (g). In some embodiments, the TNF antagonist is ENBREL (». In some embodiments, the TNF antagonist is REMICADEt).

In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGEN consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG- INTRONPEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYS@PEGylated IFN-a2a.

[00248] In some embodiments, a subject combination therapy for treating cancer in an individual comprises administering to an individual in need thereof a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts to treat the cancer. The VEGF antagonist is selected from a VEGFR tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, an anti-VEGFR ribozyme, an anti- VEGFR antisense, and an siRNA that inhibits a VEGFR. In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog. In some embodiments, the TNF antagonist is HUMIRA@. In some embodiments, the TNF antagonist is ENBREL (R). In some embodiments, the TNF antagonist is REMICADE (». In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune human IFN-ylb. In some embodiments, the Type I interferon receptor agonist is IFN-a. In some embodiments, the IFN-a is INFERGENO consensus IFN-a. In some embodiments, the IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a. In some embodiments, the IFN-a is PEG- INTRON (g) PEGylated IFN-a2b. In some embodiments, the IFN-a is PEGASYSOPEGylated IFN-a2a.

[00249] In some embodiments, a subject combination therapy for treating cancer is administered to a patient as an adjuvant to a standard cancer therapy. In some embodiments, a subject combination therapy for treating cancer involves modifying any of the above-described methods to include administration of a side-effect management agent.

FIBROTIC DISORDERS [00250] The present invention further provides methods of therapeutically treating a fibrotic disorder such as fibrosis of the lung, kidney, liver, heart, and the like in individuals who present with clinical signs of fibrotic disorder to reduce risk of death and to improve clinical functions and clinical outcomes.

[00251] In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent : In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor. In other embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist; and a tumor necrosis factor (TNF) antagonist. In other embodiments ; the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-p) antagonist. In other embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist.

[00252] Fibrosis is generally characterized by the pathologic or excessive accumulation of collagenous connective tissue. Fibrotic disorders include, but are not limited to, collagen disease, interstitial lung disease, human fibrotic lung disease (e. g. , obliterative bronchiolitis, idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, tumor stroma in lung disease, systemic sclerosis affecting the lungs, Hermansky-Pudlak syndrome, coal worker's pneumoconiosis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS-associated pulmonary hypertension, sarcoidosis, and the like), fibrotic vascular disease, arterial sclerosis, atherosclerosis, varicose veins, coronary infarcts, cerebral infarcts, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesions, human kidney disease (e. g. , nephritic syndrome, Alport's syndrome, HIV-associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus, and the like), cutis keloid formation, progressive systemic sclerosis (PSS), primary sclerosing cholangitis (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary fibrosis, cystic fibrosis, chronic graft versus host disease, scleroderma (local and systemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma, Peyronie's disease, penis fibrosis, urethrostenosis after the test using a cystoscope, inner accretion after surgery, scarring, myelofibrosis, idiopathic retroperitoneal fibrosis, peritoneal fibrosis from a known etiology, drug-induced ergotism, fibrosis incident to benign or malignant cancer, fibrosis incident to microbial infection (e. g. , viral, bacterial, parasitic, fungal, etc. ), Alzheimer's disease, fibrosis incident to inflammatory bowel disease (including stricture formation in Crohn's disease and microscopic colitis), fibrosis induced by chemical or environmental insult (e. g. , cancer chemotherapy, pesticides, radiation (e. g. , cancer radiotherapy), and the like), and the like.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat fibrotic disorders [00253] In some embodiments, a subject method for treating a fibrotic disorder involves administering a Type II interferon receptor agonist and a Type I interferon receptor agonist.

[00254] In some embodiments, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are amounts that, when co-administered to an individual having a fibrotic disorder, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the dual IFN receptor agonist therapy.

[00255] In some embodiments, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are amounts that, when administered to an individual having a fibrotic disorder, are effective to increase, or to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc.) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to dual IFN receptor agonist therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of dual IFN receptor agonist therapy.

[00256] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00257] The dual IFN receptor agonist therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

2) Type II interferon receptor agonist. SAPK inhibitor, and third therapeutic agent in combination therapy for treating fibrotic disorders [00258] The present invention further provides methods of therapeutically treating a fibrotic disorder such as fibrosis of the lung, kidney, liver, heart, and the like in individuals who present with clinical signs of fibrotic disorder to reduce risk of death and to improve clinical functions. The methods generally involve administering to an individual in need thereof an effective amount of a Type II interferon receptor agonist, an effective amount of a SAPK inhibitor (where suitable SAPK inhibitors include pirfenidone and pirfenidone analogs ; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No.

20030149041), and a third therapeutic agent (e. g. , a palliative agent or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent).

[00259] In some embodiments, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are amounts that, when co-administered to an individual having a fibrotic disorder, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the Type II interferon receptor agonist/SAPK inhibitor combination therapy.

[00260] In some embodiments, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are amounts that, when administered to an individual having a fibrotic disorder, are effective to increase, or to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to a subject combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject combination therapy.

[00261] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00262] A subject combination therapy is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat fibrotic disorders [00263] The present invention further provides methods of therapeutically treating a fibrotic disorder such as fibrosis of the lung, kidney, liver, heart, and the like in individuals who present with clinical signs of fibrotic disorder to reduce risk of death and to improve clinical functions. The methods generally involving administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist in combined effective amounts to treat the fibrotic disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune human IFN-ylb. In some embodiments, the VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. Of particular interest in many embodiments is the treatment of humans. In some embodiments, a subject method further comprises administering one or more of a Type I interferon receptor agonist, a TNF antagonist, and a SAPK inhibitor.

[00264] Fibrosis is generally characterized by the pathologic or excessive accumulation of collagenous connective tissue. Fibrotic disorders include, but are not limited to, collagen disease, interstitial lung disease, human fibrotic lung disease (e. g. , obliterative bronchiolitis, idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, tumor stroma in lung disease, systemic sclerosis affecting the lungs, Hermansky-Pudlak syndrome, coal worker's pneumoconiosis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS-associated pulmonary hypertension, sarcoidosis, and the like), fibrotic vascular disease, arterial sclerosis, atherosclerosis, varicose veins, coronary infarcts, cerebral infarcts, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesions, human kidney disease (e. g., nephritic syndrome, Alport's syndrome, HIV-associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus, and the like), cutis keloid formation, progressive systemic sclerosis (PSS), primary sclerosing cholangitis (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary fibrosis, cystic fibrosis, chronic graft versus host disease, scleroderma (local and systemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma, Peyronie's disease, penis fibrosis, urethrostenosis after the test using a cystoscope, inner accretion after surgery, scarring, myelofibrosis, idiopathic retroperitoneal fibrosis, peritoneal fibrosis from a known etiology, drug-induced ergotism, fibrosis incident to benign or malignant cancer, fibrosis incident to microbial infection (e. g. , viral, bacterial, parasitic, fungal, etc. ), Alzheimer's disease, fibrosis incident to inflammatory bowel disease (including stricture formation in Crohn's disease and microscopic colitis), fibrosis induced by chemical or environmental insult (e. g. , cancer chemotherapy, pesticides, radiation (e. g. , cancer radiotherapy), and the like), and the like.

[00265] In some embodiments, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are amounts that, when co-administered to an individual having a fibrotic disorder, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject combination therapy.

[00266] In some embodiments, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are amounts that, when administered to an individual having a fibrotic disorder, are effective to increase, or to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the baseline level of organ function in the individual prior to a subject combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject combination therapy.

[00267] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00268] A subject combination therapy is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat fibrotic disorders [00269] In some embodiments, the present invention provides methods of therapeutically treating a fibrotic disorder such as fibrosis of the lung, kidney, liver, heart, and the like in individuals who present with clinical signs of fibrotic disorder to reduce risk of death and to improve clinical functions, where the methods generally involve administering to an individual in need thereof a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, in combined effective amounts to treat the fibrotic disorder. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00270] In some embodiments, a subject combination therapy to treat a fibrotic disorder involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the fibrotic disorder. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-Y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00271] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are amounts that, when co-administered to an individual having a fibrotic disorder, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject combination therapy.

[00272] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are amounts that, when administered to an individual having a fibrotic disorder, are effective to increase, or to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the baseline level of organ function in the individual prior to a subject combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject combination therapy.

[00273] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are amounts that, when co-administered to an individual having a fibrotic disorder, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject combination therapy.

[00274] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are amounts that, when administered to an individual having a fibrotic disorder, are effective to increase, or to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 1-5%, at least about 20% . at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the baseline level of organ function in the individual prior to a subject combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject combination therapy.

[00275] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00276] A subject combination therapy is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

5) Type I or Type III interferon receptor agonist, Type II interferon receptor agonist, and TNF antagonist in combination therapy to treat fibrotic disorders [00277] In some embodiments, the present invention provides methods for treating a fibrotic disorder in an individual having a fibrotic disorder. Of particular interest in many embodiments is treatment of humans.

[00278] The method generally involves administering an effective amount of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist, and TNF-a antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

[00279] In some embodiments, effective amounts of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist and a TNF-a antagonist are amounts that, when administered in combination therapy, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment with the combination therapy or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject therapy.

[00280] In some embodiments, effective amounts of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist and a TNF-a antagonist are amounts that, when administered in combination therapy, are effective to increase, or are effective to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to treatment with the combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject therapy.

[00281] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00282] The therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

[00283] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist, and a TNF-a antagonist.

[00284] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist, and a TNF-a antagonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual, while reducing the incidence or severity of one or more side effects that would ordinarily arise from treatment with an effective amount of the Type I or III interferon receptor agonist, the Type II interferon receptor agonist, or the TNF-a antagonist alone.

6) Type II interferon receptor agonist and TNF antagonist in combination therapy to treat fibrotic disorders [00285] In some embodiments, the subject methods for treating a fibrotic disorder in an individual having a fibrotic disorder generally involve administering an effective amount of a Type II interferon receptor agonist and an effective amount of a TNF-a antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents. Of particular interest in many embodiments is treatment of humans.

[00286] In some embodiments ; effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are amounts that, when administered in combination therapy, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment with the combination therapy or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject therapy.

[00287] In some embodiments, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are amounts that, when administered in combination therapy, are effective to increase, or are effective to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to treatment with the combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject therapy.

[00288] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00289] The therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

[00290] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of a Type II interferon receptor agonist and a TNF-a antagonist.

[00291] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a Type II interferon receptor agonist and a TNF-a antagonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual, while reducing the incidence or severity of one or more side effects that would ordinarily arise from treatment with an effective amount of the Type II interferon receptor agonist or the TNF-a antagonist alone.

7) Pirfenidone and TNF antagonist in combination therapy to treat fibrotic disorders [00292] In some embodiments, the subject methods for treating a fibrotic disorder in an individual having a fibrotic disorder generally involve administering an effective amount of pirfenidone or a pirfenidone analog and TNF-a antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis.

The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents. Of particular interest in many embodiments is treatment of humans.

[00293] In some embodiments, effective amounts of a pirfenidone or a pirfenidone analog and a TNF-a antagonist are amounts that, when administered in combination therapy, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment with the combination therapy or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject therapy.

[00294] In some embodiments, effective amounts of pirfenidone or a pirfenidone analog and a TNF-a antagonist are amounts that, when administered in combination therapy, are effective to increase, or are effective to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to treatment with the combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject therapy.

[00295] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00296] The therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

[00297] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of pirfenidone or a pirfenidone analog and a TNF-a antagonist.

[00298] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of pirfenidone or a pirfenidone analog and a TNF-a antagonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual, while reducing the incidence or severity of one or more side effects that would ordinarily arise from treatment with an effective amount of pirfenidone (or a pirfenidone analog) or the TNF-a antagonist alone.

8) Type II interferon receptor agonist and TGF-I} antagonist in combination therapy to treat fibrotic disorders [00299] In some embodiments, the subject methods for treating a fibrotic disorder in an individual having a fibrotic disorder generally involve administering an effective amount of a Type II interferon receptor agonist and a TGF- (3 antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents. Of particular interest in many embodiments is treatment of humans.

[00300] In some embodiments, effective amounts of a Type II interferon receptor agonist and a TGF-P antagonist are amounts that, when administered in combination therapy, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment with the combination therapy or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject therapy.

[00301] In some embodiments, effective amounts of a Type II interferon receptor agonist and a TGF- (3 antagonist are amounts that, when administered in combination therapy, are effective to increase, or are effective to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to treatment with the combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject therapy.

[00302] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00303] The therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

[00304] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of a Type II interferon receptor agonist and a TGF- (3 antagonist.

[00305] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a Type II interferon receptor agonist and a TGF- (3 antagonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual, while reducing the incidence or severity of one or more side effects that would ordinarily arise from treatment with an effective amount of the Type II interferon receptor agonist or TGF- (3 antagonist alone.

9) SAPK inhibitors in monotherapy and combination therapy for the treatment of fibrotic disorders [00306] In some embodiments, the subject methods for treating a fibrotic disorder in an individual having a fibrotic disorder generally involve administering an effective amount of an agent that inhibits a stress-activated protein kinase (SAPK), otherwise referred to herein as"a SAPK inhibitor, "e. g. , the agent inhibits enzymatic activity of a SAPK, where the SAPK inhibitor is other than pirfenidone or a pirfenidone analog, and where the SAPK inhibitor is other than a compound of Formula I as set forth in U. S. Patent Publication No. 20030149041.

The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents. Of particular interest in many embodiments is treatment of humans.

[00307] In some embodiments, an effective amount of a SAPK inhibitor is an amount that, when administered in a subject SAPK inhibitor therapy, is effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment with the subject SAPK inhibitor therapy or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject therapy.

[00308] In some embodiments, an effective amount of a SAPK inhibitor is an amount that, when administered in a subject SAPK inhibitor therapy, is effective to increase, or is effective to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to treatment with the subject SAPK inhibitor therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject therapy.

[00309] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00310] The therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

[00311] In some embodiments, the present invention provides methods of treating a fibrotic disease in an individual having a fibrotic disease, the method generally involving administering to the individual a SAPK inhibitor and a Type II interferon receptor agonist in a combined dosage effective to treat the fibrotic disease.

[00312] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of a SAPK inhibitor and a Type II interferon receptor agonist.

[00313] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a SAPK inhibitor and a Type II interferon receptor agonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00314] In some embodiments, a subject method featuring administration of a SAPK inhibitor and a Type II interferon receptor agonist is modified to include administration of a Type I interferon receptor agonist. Thus, in some embodiments, the invention provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00315] In some embodiments, the present invention provides methods of treating a fibrotic disease in an individual, the method generally involving administering to the individual a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab, or adalimumab) in a combined dosage effective to treat the fibrotic disease.

[00316] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab, or adalimumab).

[00317] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab, or adalimumab) that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00318] In some embodiments, the present invention provides methods of treating a fibrotic disease in an individual, the method generally involving administering to the individual a SAPK inhibitor and a TGF-ß antagonist (e. g., GLEEVECTMimatinib mesylate) in a combined dosage effective to treat the fibrotic disease.

[00319] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of a SAPK inhibitor and a TGF- ß antagonist (e.g., GLEEVECTM imatinib mesylate).

[00320] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a SAPK inhibitor and a TGF-ß antagonist (e. g., GLEEVECTM imatinib mesylate) that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00321] In some embodiments, the present invention provides methods of treating a fibrotic disease in an individual, the method generally involving administering to the individual a SAPK inhibitor and an endothelin receptor antagonist (e. g., TRACLEERTM bosentan) in a combined dosage effective to treat the fibrotic disease.

[00322] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of a SAPK inhibitor and an endothelin receptor antagonist (e. g., TRACLEERTM bosentan).

[00323] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a SAPK inhibitor and an endothelin receptor antagonist (e. g., TRACLEERTM bosentan) that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

10) N-acetyl cysteine and SAPK inhibitor in combination therapy for treating fibrotic disorders [00324] In some embodiments, the subject methods for treating a fibrotic disorder in an individual having a fibrotic disorder generally involve administering an effective combination of N-acetylcytsteine (NAC) and an agent that inhibits a stress-activated protein kinase (SAPK), otherwise referred to herein as"a SAPK inhibitor" (where suitable SAPK inhibitors include pirfenidone and pirfenidone analogs; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No. 20030149041). The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis.

The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents. Of particular interest in many embodiments is treatment of humans.

[00325] Without being limited to any particular mechanism of action, it is believed that NAC and SAPK inhibitor combination therapy will provide additive or synergistic down modulation of inflammatory processes that contribute to the pathogenesis of fibrotic disorders. SAPK is an Ff 'hmR l.n m',.",.......- important mediator of TNFR signal transduction. Thus, a SAPK inhibitor is expected to downregulate TNF activation of inflammatory processes involved in the etiology of fibrotic disease. As a scavenger of free radicals, NAC is expected to reduce the destruction of tissue caused by non-specific immune cell activity at disease sites. In addition, NAC can inhibit free radical-mediated activation ofNF-xB, a potent inducer of TNF-a. Therefore, NAC is expected to reduce blood levels of TNF and TNF-mediated inflammation. Since NAC and SAPK inhibitor intervene at different stages-of the inflammatory cascade, it is believed that combination therapy with these agents will achieve an additive or synergistic improvement in clinical outcome compared to monotherapy with either agent in the treatment of fibrotic disorders.

[00326] In some embodiments, the present invention provides methods of treating a fibrotic condition that involves administering a synergistic combination of NAC and a SAPK inhibitor.

[00327] In some embodiments, effective amounts of a SAPK inhibitor and NAC are any combined dosage that is effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment with the subject NAC and SAPK inhibitor combination therapy or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject therapy.

[00328] In some embodiments, effective amounts of a SAPK inhibitor and NAG are any combined dosage that is effective to increase, or is effective to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to treatment with the NAC and SAPK inhibitor combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject therapy.

[00329] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00330] The therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

[00331] In some embodiments, the present invention provides methods of treating a fibrotic disease in an individual having a fibrotic disease, the method generally involving administering to the individual NAC, a SAPK inhibitor and a Type II interferon receptor agonist in a combined dosage effective to treat the fibrotic disease.

[00332] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of NAC, a SAPK inhibitor and a Type II interferon receptor agonist.

[00333] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of NAC, a SAPK inhibitor and a Type II interferon receptor agonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00334] In some embodiments, a subject method featuring administration of NAC, a SAPK inhibitor and a Type II interferon receptor agonist is modified to include administration of a Type I interferon receptor agonist. Thus, in some embodiments, the invention provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00335] In some embodiments, the present invention provides methods of treating a fibrotic disease in an individual, the method generally involving administering to the individual NAC, a SAPK inhibitor and a TNF antagonist (e. g., etanercept, infliximab, or adalimumab) in a combined dosage effective to treat the fibrotic disease.

[00336] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of NAC, a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab, or adalimumab).

[00337] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of NAC, a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab, or adalimumab) that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.- [00338] In some embodiments, the present invention provides methods of treating a fibrotic disease in an individual, the method generally involving administering to the individual NAC, a SAPK inhibitor and a TGF-ß antagonist (e. g., GLEEVECTMimatinib mesylate) in a combined dosage effective to treat the fibrotic disease.

[00339] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of NAC, a SAPK inhibitor and a TGF- (3 antagonist (e. g., GLEEVECTM imatinib mesylate).

[00340] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of NAC, a SAPK inhibitor and a TGF-P antagonist (e. g., GLEEVECTM imatinib mesylate) that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00341] In some embodiments, the present invention provides methods of treating a fibrotic disease in an individual, the method generally involving administering to the individual NAC, a SAPK inhibitor and an endothelin receptor antagonist (e. g., TRACLEERTM bosentan) in a combined dosage effective to treat the fibrotic disease.

[00342] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of NAC, a SAPK inhibitor and an endothelin receptor antagonist (e. g., TRACLEERTM bosentan).

[00343] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of NAC, a SAPK inhibitor and an endothelin receptor antagonist (e. g., TRACLEERTM bosentan) that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

11) N-acetyl cysteine and Type II interferon receptor agonist in combination therapy for treating fibrotic disorders [00344] In some embodiments, subject methods for treating a fibrotic disorder in an individual having a fibrotic disorder generally involve administering an effective amount of a Type II interferon receptor agonist and N-acetylcysteine (NAC). The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis.

The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents. Of particular interest in many embodiments is treatment of humans.

[00345] Without being limited to any particular mechanism of action, it is believed that NAC and Type II interferon receptor agonist combination therapy will provide additive or synergistic benefit in the treatment of fibrotic disorders. As demonstrated below, IFN-y is an anti-fibrotic agent that downregulates TGF-ß-induced collagen deposition. Thus, IFN-is expected to inhibit or curtail the dysregulated collagen production involved in the etiology of fibrotic disease. However, IFN-y is also a potent activator of non-specific immune cells that can contribute to inflammation at disease sites. The pro-inflammatory activity of IFN-y could augment the inflammatory processes involved in the etiology of fibrotic disease, thereby limiting the effectiveness of IFN-y in the treatment of fibrotic disorders.

[00346] As a scavenger of free radicals, NAC is expected to reduce the destruction of tissue caused by non-specific immune cell activity at disease sites. It is believed that the anti- inflammatory activity of NAC can offset or mitigate any inflammation induced by exogenously administered IFN-y, thereby increasing the therapeutic index of IFN-y in the treatment of fibrotic disorders. In addition, NAC can inhibit free radical-mediated activation of NF-KB, a potent inducer of TNF-a. Therefore, NAC is expected to reduce blood levels of TNF and TNF-mediated inflammation. Since NAC and IFN-y act on different processes in the pathogenesis of fibrotic disorders, and since NAC has the potential to increase the therapeutic index of IFN-y, it is believed that combination therapy with these agents will achieve an additive or synergistic improvement in clinical outcome compared to monotherapy with either agent in the treatment of fibrotic disorders.

[00347] In some embodiments, effective amounts of a Type II interferon receptor agonist and NAC are amounts that, when administered in combination therapy, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment with the combination therapy or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject therapy.

[00348] In some embodiments, effective amounts of a Type II interferon receptor agonist and NAC are amounts that, when administered in combination therapy, are effective to increase, or are effective to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e. g. , lung, liver, kidney, etc. ) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%,-at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to treatment with the combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject therapy.

[00349] Methods of measuring-the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[00350] The therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

[00351] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of a Type II interferon receptor agonist and NAC.

[00352] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of a Type II interferon receptor agonist and NAC that is effective for prophylaxis or therapy of fibrotic disease in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual, while reducing the incidence or severity of one or more side effects that would ordinarily arise from treatment with an effective amount of a Type II interferon receptor agonist or NAC alone.

Idiopathic Pulmonary Fibrosis [00353] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II-interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor. In other embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist ; and a tumor necrosis factor (TNF) antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-ß) antagonist. In other embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist.

[00354] In some embodiments, a diagnosis of IPF is confirmed by the finding of usual interstitial pneumonia (UIP) on histopathological evaluation of lung tissue obtained by surgical biopsy. The criteria for a diagnosis of IPF are known. Ryu et al. (1998) Mayo Clin. Proc.

73: 1085-1101.

[00355] In other embodiments, a diagnosis of IPF is a definite or probable IPF made by high resolution computer tomography (HRCT). In a diagnosis by HRCT, the presence of the following characteristics is noted: (1) presence of reticular abnormality and/or traction bronchiectasis with basal and peripheral predominance; (2) presence of honeycombing with basal and peripheral predominance ; and (3) absence of atypical features such as micronodules, peribronchovascular nodules, consolidation, isolated (non-honeycomb) cysts, ground glass attenuation (or, if present, is less extensive than reticular opacity), and mediastinal adenopathy (or, if present, is not extensive enough to be visible on chest x-ray). A diagnosis of definite IPF is made if characteristics (1), (2), and (3) are met. A diagnosis of probable IPF is made if characteristics (1) and (3) are met.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat IPF [00356] In some embodiments, a subject method for treating IPF involves administering to an individual having IPF effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist.

[00357] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[003581 Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLco. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00359] Thus, e. g., where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00360] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00361] In some embodiments, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , an effective amount of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00362] In some embodiments, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25% j at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00363] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00364] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that increases the single breath DLco by at least about 15 %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5- fold, or more, compared to baseline. DLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00365] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVl) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00366] Lung function can be measured using any known method, including, but not limited to spirometry.

2) Type II interferon receptor agonist, SAPK inhibitor, and third therapeutic avent in combination therapy for treating IPF [00367] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involve administering to an individual having IPF an effective amount of a Type II interferon receptor agonist, an effective amount of a SAPK inhibitor, and a third therapeutic agent (e. g. , a palliative agent or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent).

[00368] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00369] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLco. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00370] Thus, e. g. , where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a Type II interferon receptor agonist and a SAPK inhibitor exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00371] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at- least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00372] In some embodiments, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , an effective amount of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00373] In some embodiments, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00374] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm, Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00375] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that increases the single breath DLco by at least about 15 %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00376] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVl) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00377] Lung function can be measured using any known method, including, but not limited to spirometry.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat IPF [00378] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involving administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune human IFN-ylb. In some embodiments, the VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR.

[00379] In some embodiments, a diagnosis of IPF is confirmed by the finding of usual interstitial pneumonia (UIP) on histopathological evaluation of lung tissue obtained by surgical biopsy. The criteria for a diagnosis of IPF are known. Ryu et al. (1998) Mayo Clin. Proc.

73: 1085-1101.

[00380] In other embodiments, a diagnosis of IPF is a definite or probable IPF made by high resolution computer tomography (HRCT). In a diagnosis by HRCT, the presence of the following characteristics is noted: (1) presence of reticular abnormality and/or traction bronchiectasis with basal and peripheral predominance; (2) presence of honeycombing with basal and peripheral predominance; and (3) absence of atypical features such as micronodules, peribronchovascular nodules, consolidation, isolated (non-honeycomb) cysts, ground glass attenuation (or, if present, is less extensive than reticular opacity), and mediastinal adenopathy (or, if present, is not extensive enough to be visible on chest x-ray). A diagnosis of definite IPF is made if characteristics (1), (2), and (3) are met. A diagnosis of probable IPF is made if characteristics (1) and (3) are met.

[00381] In some embodiments,"effective amounts"of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00382] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLco. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00383] Thus, in some embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a Type II interferon receptor agonist and a VEGF antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00384] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00385] In some embodiments, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a Type II interferon receptor agonist and a VEGF antagonist include any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5- fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00386] In some embodiments, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00387] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00388] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that increases the single breath DLeo by at least about 15 %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00389] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVI) ; total lung capacity; partial pressure of arterial oxygen at rest ; partial pressure of arterial oxygen at maximal exertion.

[00390] Lung function can be measured using any known method, including, but not limited to spirometry.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat IPF [00391] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involve administering to an individual in need thereof a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, in combined effective amounts to treat the IPF. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00392] In some embodiments, a subject combination therapy to treat IPF involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the IPF. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00393] In some embodiments, a diagnosis of IPF is confirmed by the finding of usual interstitial pneumonia (UIP) on histopathological evaluation of lung tissue obtained by surgical biopsy. The criteria for a diagnosis of IPF are known. Ryu et al. (1998) Mayo Clin. Proc.

73: 1085-1101.

[00394] In other embodiments, a diagnosis of IPF is a definite or probable IPF made by high resolution computer tomography (HRCT). In a diagnosis by HRCT, the presence of the following characteristics is noted: (1) presence of reticular abnormality and/or traction bronchiectasis with basal and peripheral predominance; (2) presence of honeycombing with basal and peripheral predominance; and (3) absence of atypical features such as micronodules, peribronchovascular nodules, consolidation, isolated (non-honeycomb) cysts, ground glass attenuation (or, if present, is less extensive than reticular opacity), and mediastinal adenopathy (or, if present, is not extensive enough to be visible on chest x-ray). A diagnosis of definite IPF is made if characteristics (1), (2), and (3) are met. A diagnosis of probable IPF is made if characteristics (1) and (3) are met.

[00395] In some embodiments, "effective amounts"of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00396] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLco. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00397] Thus, in some embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00398] In some embodiments, "effective amounts"of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00399] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00400] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00401] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00402] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that increases the single breath DLCo by at least about 15 %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. CLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00403] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEV1) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00404] Lung function can be measured using any known method, including, but not limited to spirometry.

[00405] In other embodiments, any of the above-described methods of treating IPF can be modified to further comprise administering an amount of at least one additional anti-fibrotic agent effective to augment the anti-fibrotic treatment received by the individual. In some of these embodiments, the additional anti-fibrotic agent is selected from a TGF-f3 antagonist, an endothelin receptor antagonist, and N-acetylcysteine (NAC).

5) Type I or TyPe III interferon receptor agonist, Tvpe II interferon receptor agonist, and TNF antagonist in combination therapy to treat IPF [00406] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involve administering to an individual having IPF effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist.

[00407] In some embodiments, "effective amounts"of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%,-at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00408] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLeo. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00409] Thus, e. g. , where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00410] In some embodiments, "effective amounts"of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00411] In some embodiments, effective amounts of a Type II interferon receptor agonist, a Type I interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00412] In some embodiments, effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00413] In some of these embodiments, effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00414] In some of these embodiments, effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that increases the single breath DLeo by at least about 15 %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4- fold, at least about 5-fold, or more, compared to baseline. DLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00415] Parameters of lung function include, but are not limited to, forced vital capacity (FVC) ; forced expiratory volume (FEVl) ; total lung-capacity ; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00416] Lung function can be measured using any known method, including, but not limited to spirometry.

[00417] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of-individuals having IPF who were treated with corticosteroids within the previous 24 months, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art.

See, e. g. , Crapo et al, (1981) Am. Rev. Respir. Dis., 123: 659-664. FVC is measured using standards methods of spirometry.

[00418] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLCo) zu 25%, or > 35%, of predicted normal DLco.

[00419] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco > 35% of predicted normal DLco and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

6) Type II interferon receptor agonist and TNF antagonist in combination therapy to treat IPF [00420] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involve administering to an individual having IPF effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist.

[00421] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00422] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more ; (3) a decrease of 15% or more in single breath DLco. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00423] Thus, e. g. , where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a Type II interferon receptor agonist and a TNF-a antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00424] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00425] In some embodiments, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00426] In some embodiments, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about-4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00427] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00428] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that increases the single breath DLco by at least about 15 %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00429] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVI) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00430] Lung function can be measured using any known method, including, but not limited to spirometry.

[00431] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were treated with corticosteroids within the previous 24 months, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art.

See, e. g. , Crapo et al, (1981) Am. Rev. Respir. Dis., 123: 659-664. FVC is measured using standards methods of spirometry.

[00432] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) zu 25%, or > 35%, of predicted normal DLco.

[00433] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco > 35% of predicted normal DLCo and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

7) Pirfenidone and TNF antagonist in combination therapy to treat IPF [00434] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involve administering to an individual having IPF effective amounts of pirfenidone (or a pirfenidone analog) and a TNF-a antagonist.

[00435] In some embodiments, "effective amounts"of pirfenidone or a pirfenidone analog and a TNF-a antagonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00436] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLeo. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00437] Thus, e. g. , where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of pirfenidone or a pirfenidone analog, and a TNF-a antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00438] In some embodiments, "effective amounts"of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about-10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00439] In some embodiments, effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00440] In some embodiments, effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00441] In some of these embodiments, effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00442] In some of these embodiments, effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that increases the single breath DLeo by at least about 15 %, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DLo is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00443] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVI) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00444] Lung function can be measured using any known method, including, but not limited to spirometry.

[00445] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were treated with corticosteroids within the previous 24 months, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art.

See, e. g. , Crapo et al, (1981) Am. Rev. Respir. Dis., 123: 659-664. FVC is measured using standards methods of spirometry.

[00446] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) zu 25%, or > 35%, of predicted normal DLco.

[00447] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco > 35% of predicted normal DLco and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

8) Type II interferon receptor agonist and TGF-I} antagonist in combination therapy to treat IPF [00448] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involve administering to an individual having IPF effective amounts of a Type II interferon receptor agonist, and a TGF- (3 antagonist.

[00449] In some embodiments, "effective amounts"of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00450] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLo. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00451] Thus, e. g. , where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a Type II interferon receptor agonist, and a TGF-P antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00452] In some embodiments, "effective amounts"of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00453] In some embodiments, effective amounts of a Type II interferon receptor agonist, and a TGF-P antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a Type II interferon receptor agonist, and a TGF-P antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00454] In some embodiments, effective amounts of a Type II interferon receptor agonist, and a TGF-ß antàgonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00455] In some of these embodiments, effective amounts of a Type II interferon receptor agonist, and a TGF-P antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00456] In some of these embodiments, effective amounts of a Type II interferon receptor agonist, and a TGF- (3 antagonist are any combined dosage that increases the single breath DLeo by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00457] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVl) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00458] Lung function can be-measured using any known method, including, but not limited to spirometry.

[00459] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were treated with corticosteroids within the previous 24 months, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art.

See, e. g. , Crapo et al, (1981) Am. Rev. Respir. Dis., 123: 659-664. FVC is measured using standards methods of spirometry.

[00460] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) zu 25%, or > 30%, or >-35%, of predicted normal DLCO.

[00461] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLCo > 35% of predicted normal DLCO and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

[00462] Additionally suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco > 30% of predicted normal DLCO and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

9) SAPK inhibitors in monotherapy and combination therapy for the treatment of IPF [00463] In some embodiments, the present invention provides methods of treating idiopathic pulmonary fibrosis (IPF). The methods generally involve administering to an individual having IPF an effective amount of a SAPK inhibitor. In these embodiments, the method generally involves administering an effective amount of an agent that inhibits a stress-activated protein kinase (SAPK), otherwise referred to herein as"a SAPK inhibitor, "e. g., the agent inhibits enzymatic activity of a SAPK, where the SAPK inhibitor is other than pirfenidone or a pirfenidone analog, and where the SAPK inhibitor is other than a compound of Formula I as set forth in U. S. Patent Publication No. 20030149041.

[00464] In another aspect, the present invention provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist. The present invention also provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist.

[00465] In another aspect, the present invention provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab or adalimumab).

[00466] In another aspect, the present invention provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of a SAPK inhibitor and a TGF-P antagonist (e. g. , imatinib mesylate).

[00467] In another aspect, the present invention provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of a SAPK inhibitor and an endothelin receptor antagonist (e. g. , bosentan).

[00468] In some embodiments, "an effective amount"of a SAPK inhibitor is any dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00469] In some embodiments, "effective amounts"of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00470] In some embodiments, "effective amounts"of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00471] In some embodiments, "effective amounts"of a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab or adalimumab) are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00472] In some embodiments, "effective amounts"of a SAPK inhibitor and a TGF-ß antagonist (e. g. , imatinib mesylate) are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00473] In some embodiments, "effective amounts"of a SAPK inhibitor and an endothelin receptor antagonist (e. g. , bosentan) are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00474] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more ; (3) a decrease of 15% or more in single breath DL... Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00475] Thus, e. g. , where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective a SAPK inhibitor exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00476] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a SAPK inhibitor and a Type II interferon receptor agonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00477] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00478] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a SAPK inhibitor and a TNF antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00479] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a SAPK inhibitor and a TGF-P antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00480] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a SAPK inhibitor and an endothelin receptor antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00481] In some embodiments, "an effective amount"of a SAPK inhibitor is any dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments an effective amount of a SAPK inhibitor is any dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00482] In some embodiments, "effective amounts"of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase progression- free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00483] In some embodiments,"effective amounts"of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00484] In some embodiments, "effective amounts"of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3- fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00485] In some embodiments, "effective amounts"of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo- treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00486] In some embodiments, "effective amounts"of a SAPK inhibitor and endothelin receptor antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00487] In some embodiments, an effective amount of a SAPK inhibitor is any dosage that is effective to increase at least one parameter of lung function, e. g. , an effective amount of a SAPK inhibitor is any dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated-individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g., 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

8] In some embodiments, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

9] In some embodiments, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

0] In some embodiments, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g., effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00491] In some embodiments, effective amounts of a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00492] In some embodiments, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g., 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00493] In some embodiments, an effective amount of a SAPK inhibitor is any dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00494] In some embodiments, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00495] In some embodiments, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00496] In some embodiments, effective amounts of a SAPK inhibitor and TNF antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00497] In some embodiments, effective amounts of a SAPK inhibitor and a TGF-P antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00498] In some embodiments, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold ; or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00499] In some embodiments, an effective amount of a SAPK inhibitor is any dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00500] In other embodiments, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00501] In other embodiments, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00502] In other embodiments, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00503] In other embodiments, effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00504] In other embodiments, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that results in a decrease in alveolar : arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00505] In some embodiments, an effective amount of a SAPK inhibitor is any dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00506] In other embodiments, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00507] In other embodiments, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00508] In other embodiments, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that increases the single breath DLCo by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00509] In other embodiments, effective amounts of a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3- fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00510] In other embodiments, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00511] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEV1) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00512] Lung function can be measured using any known method, including, but not limited to spirometry.

[00513] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were treated with corticosteroids within the previous 24 months,, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art.

See, e. g. , Crapo et al, (1981) Am. Rev. Respir. Dis., 123: 659-664. FVC is measured using standards methods of spirometry.

[00514] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) > 25%, or > 30%, or > 35%, of predicted normal DLco.

[00515] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco > 35% of predicted normal DLCO and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

[00516] Additionally suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco zu 30% of predicted normal DLCo and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

10) N-acetyl cysteine and SAPK inhibitor in combination therapy for treating IPF [00517] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involve administering to an individual having IPF effective amount of NAC and a SAPK inhibitor.

[00518] In another aspect, the present invention provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist. The present invention also provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of NAC, a SAPK inhibitor,-a Type II interferon receptor agonist, and a Type I interferon receptor agonist.

[00519] In another aspect, the present invention provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of NAC, a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab or adalimumab).

[00520] In another aspect, the present invention provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of NAC, a SAPK inhibitor and a TGF-P antagonist (e. g. , imatinib mesylate).

[00521] In another aspect, the present invention provides methods of treating IPF, the methods generally involving administering to an individual having IPF effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist (e. g. , bosentan).

[00522] In some embodiments,"effective amounts"of NAC and a SAPK inhibitor are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00523] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00524] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00525] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab or adalimumab) are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00526] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor and a TGF-ß antagonist (e. g. , imatinib mesylate) are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00527] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor and an endothelin receptor antagonist (e. g. , bosentan) are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00528] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DLeo. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00529] Thus, e. g. , where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with effective amounts of NAC and a SAPK inhibitor exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00530] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of NAC, a SAPK inhibitor and a Type II interferon receptor agonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00531] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00532] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of NAC, a SAPK inhibitor and a TNF antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00533] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of NAC, a SAPK inhibitor and a TGF-ß antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00534] In other embodiments, where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of NAC, a SAPK inhibitor and an endothelin receptor antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00535] In some embodiments,"effective amounts"of NAC and a SAPK inhibitor are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00536] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase progression- free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00537] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase progression-free survival time, e. g., the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual.

Thus, e. g. , in some embodiments effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00538] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo- treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00539] In some embodiments, "effective amounts"of NAC, a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo- treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of NAC, a SAPK inhibitor and a TGF-P antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00540] In some embodiments,"effective amounts"of NAC, a SAPK inhibitor and endothelin receptor antagonist are any combined dosage that is effective to increase progression-free survival time, e. g. , the time from baseline (e. g., a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00541] In some embodiments, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to increase at least one parameter of lung function, e. g., an effective amount of a SAPK inhibitor is any dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00542] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00543] In some embodiments, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist-are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00544] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at-any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00545] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of NAC, a SAPK inhibitor and a TGF-P antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00546] In some embodiments, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g. , 48 weeks after the beginning of treatment, or between two time points, e. g., about 4 to about 14 weeks apart, after the beginning of treatment.

[00547] In some embodiments, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00548] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00549] In some embodiments, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00550] In some embodiments, effective amounts of NAC, a SAPK inhibitor and TNF antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00551] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00552] In some embodiments, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold,-at least about 3-fold, at least about 4-fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00553] In some embodiments, effective amounts of NAC and a SAPK inhibitor are any dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00554] In other embodiments, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00555] In other embodiments, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00556] In other embodiments, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00557] In other embodiments, effective amounts of NAC, a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00558] In other embodiments, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00559] In some embodiments, effective amounts of NAC and a SAPK inhibitor is any dosage that increases the single breath DLeo by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DLco is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00560] In other embodiments, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that increases the single breath DLeo by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00561] In other embodiments, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00562] In other embodiments, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that increases the single breath DLeo by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00563] In other embodiments, effective amounts of NAC, a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00564] In other embodiments, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.

[00565] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVI) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00566] Lung function can be measured using any known method, including, but not limited to spirometry.

[00567] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were treated with corticosteroids within the previous 24 months, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art.

See, e. g. , Crapo et al, (1981) Am. Rev. Respir. Dis., 123: 659-664. FVC is measured using standards methods of spirometry.

[00568] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) zu 25%, or > 30%, or > 35%, of predicted normal DLCO.

[00569] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco 35% of predicted normal DLCo and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

[00570] Additionally suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco zu 30% of predicted normal DLco and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

11) N-acetyl cysteine and Type II interferon receptor agonist in combination therapy for treating IPF [00571] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF).

The methods generally involve administering to an individual having IPF effective amounts of a Type II interferon receptor agonist, and N-acetylcysteine (NAC).

[00572] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[00573] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more ; (2) an increase in A-a gradient of 5 mm Hg or more ; (3) a decrease of 15% or more in single breath DLCow Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[00574] Thus, e. g. , where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of a Type II interferon receptor agonist and NAC exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[00575] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to increase progression-free survival time, e. g., the time from baseline (e. g. , a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3- fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual. Thus, e. g. , in some embodiments effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[00576] In some embodiments, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to increase at least one parameter of lung function, e. g. , effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e. g., 48 weeks after the beginning of treatment, or between two time points, e. g. , about 4 to about 14 weeks apart, after the beginning of treatment.

[00577] In some embodiments, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to increase the FVC by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[00578] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that results in a decrease in alveolar: arterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[00579] In some of these embodiments, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that increases the single breath DLco by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DLeo is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[00580] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEV1) ; total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[00581] Lung function can be measured using any known method, including, but not limited to spirometry.

[00582] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were treated with corticosteroids within the previous 24 months, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art.

See, e. g. , Crapo et al, (1981) Am. Rev. Respir. Dis., 123: 659-664. FVC is measured using standards methods of spirometry.

[00583] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) zu 25%, or > 30%, or > 35%, of predicted normal DLco.

[00584] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco zu 35% of predicted normal DLCO and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

[00585] Additionally suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco 30% of predicted normal DLCO and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

Liver Fibrosis [00586] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor. In other embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist ; and a tumor necrosis factor (TNF) antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-ß) antagonist. In other embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist. Of particular interest in many embodiments is treatment of humans.

[00587] Liver fibrosis is a precursor to the complications associated with liver cirrhosis, such as portal hypertension, progressive liver insufficiency, and hepatocellular carcinoma. A reduction in liver fibrosis thus reduces the incidence of such complications. Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop complications associated with cirrhosis of the liver.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat liver fibrosis [00588] In some embodiments, the present methods for treating liver fibrosis generally involve administering therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist. As used herein,'"effective amounts"of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective in reducing liver fibrosis or reduce the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00589] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00590] Whether treatment with a combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function.

Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by"grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long-term disease progression. See, e. g. , Brunt (2000) Hepatol. 31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00591] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00592] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00593] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score : 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J : Hepatol. 13: 372.

[00594] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00595] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00596] In some embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies.

In particular embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00597] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with dual IFN receptor agonist therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00598] In another embodiment, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00599] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00600] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of- the marker in an untreated individual, or in a placebo-treated individual.

[00601] Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00602] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with dual IFN receptor agonist therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00603] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequellae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00604] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00605] Whether combination therapy with a Type II interferon receptor agonist and a Type I interferon receptor agonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the-art.

[00606] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g. , albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[00607] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00608] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00609] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. Therapeutically effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

2) Type II interferon receptor asonist, SAPK inhibitor, and third therapeutic agent in combination therapy for treating liver fibrosis [00610] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering to an individual having liver fibrosis an effective amount of a Type II interferon receptor agonist, an effective amount of a SAPK inhibitor, and a third therapeutic agent (e. g. , a palliative agent or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent).

Of particular interest in many embodiments is treatment of humans.

[00611] The present methods generally involve administering therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor. As used herein,"effective amounts"of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective in reducing liver fibrosis or reduce the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00612] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a Type II interferon receptor agonist and a SAPK inhibitor that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00613] Whether treatment with a combination of a Type II interferon receptor agonist and a SAPK inhibitor is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long- term disease progression. See, e. g., Brunt (2000) Hepatol. 31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00614] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation) ; bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows : score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation ; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00615] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: 1. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation ; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis ; score : 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00616] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) R Hepatol. 13: 372.

[00617] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00618] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00619] In some embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00620] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with a subject combination therapy. Morphometric computerized semi- automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00621] In another embodiment, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00622] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00623] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00624] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with Type II interferon receptor agonist/SAPK inhibitor combination therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00625] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequellae of decompensated liver disease, i. e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00626] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00627] Whether combination therapy with a Type II interferon receptor agonist and a SAPK inhibitor is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00628] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics ; and the like.

[00629] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00630] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00631] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat liver fibrosis [00632] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involving administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist in combined effective amounts to treat the liver fibrotic disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the IFN-y is Actimmune (g human IFN-ylb. In some embodiments, the VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR.

[00633] Liver fibrosis is a precursor to the complications associated with liver cirrhosis, such as portal hypertension, progressive liver insufficiency, and hepatocellular carcinoma. A reduction in liver fibrosis thus reduces the incidence of such complications. Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop complications associated with cirrhosis of the liver.

[00634] The present methods generally involve administering therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist. In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00635]'The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a Type II interferon receptor agonist and a VEGF antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00636] Whether treatment with a combination of a Type II interferon receptor agonist and a VEGF antagonist is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long- term disease progression. See, e. g., Brunt (2000) Hepatol. 31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00637] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation) ; bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00638] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation ; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00639] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J : Hepatol. 13: 372.

[00640] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00641] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00642] In some embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00643] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with a subject combination therapy. Morphometric computerized semi- automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00644] In another embodiment, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00645] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00646] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00647] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with dual IFN receptor agonist therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00648] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequelae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00649] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00650] Whether combination therapy with a Type II interferon receptor agonist and a VEGF antagonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00651] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[00652] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00653] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00654] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, in some embodiments therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. In other embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat liver fibrosis [00655] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering to an individual in need thereof a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, in combined effective amounts to treat the liver fibrosis. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00656] In some embodiments, a subject combination therapy to treat liver fibrosis involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the liver fibrosis. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00657] Liver fibrosis is a precursor to the complications associated with liver cirrhosis, such as portal hypertension, progressive liver insufficiency, and hepatocellular carcinoma. A reduction in liver fibrosis thus reduces the incidence of such complications. Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop complications associated with cirrhosis of the liver.

[00658] The present methods generally involve administering therapeutically effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor. In some embodiments, "effective amounts"of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective in reducing liver fibrosis or reduce the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00659] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00660] Whether treatment with a combination of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by"grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage"as being reflective of long-term disease progression. See, e. g. , Brunt (2000) Hepatol.

31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00661] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00662] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation ; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion) ; score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00663] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13: 372.

[00664] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00665] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00666] In some embodiments, therapeutically effective amounts of a TNF antagonist and a VEGF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a TNF antagonist and a VEGF antagonist, or a VEGF antagonist and a SAPK inhibitor, reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00667] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with a subject combination therapy. Morphometric computerized semi- automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00668] In another embodiment, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00669] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III. peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00670] In another embodiment, therapeutically effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00671] Quantitative tests of functional liver reserve can also be used to assess the efficacy-of treatment with dual IFN receptor agonist therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00672] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequelae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00673] In another embodiment, therapeutically effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00674] Whether combination therapy with a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00675] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g. , albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism ; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics ; and the like.

[00676] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00677] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00678] In another embodiment, therapeutically effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about. 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, in some embodiments therapeutically effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. In some embodiments, therapeutically effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00679] In other embodiments, any of the above-described methods of treating liver fibrosis can be modified to further comprise administering an amount of at least one additional anti-fibrotic agent effective to augment the anti-fibrotic treatment received by the individual. In some of these embodiments, the additional anti-fibrotic agent is selected from a TGF-ß antagonist, an endothelin receptor antagonist, and N-acetylcysteine (NAC).

5) Type I or Type III interferon receptor agonist, Type II interferon receptor agonist, and TNF antagonist in combination therapy to treat liver fibrosis [00680] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering an effective combination of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist to an individual in need thereof. Of particular interest in many embodiments is treatment of humans.

[00681] The present methods generally involve administering therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF- a antagonist. As used herein, "effective amounts"of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist ; and-a TNF-a antagonist are any combined dosage that is effective in reducing liver fibrosis or reduce the rate of progression of liver fibrosis ; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis ; and/or that is effective in reducing a parameter associated with liver fibrosis ; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00682] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00683] Whether treatment with a combination of a Type II interferon receptor agonist, a Type I interferon receptor agonist, and a TNF-a antagonist is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by"grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage"as being reflective of long-term disease progression. See, e. g., Brunt (2000) Hepatol.

31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00684] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis) ; necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration) ; inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00685] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00686] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture ; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J HepatoL 13: 372.

[00687] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00688] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00689] In some embodiments, therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF- a antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00690] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00691] In another embodiment, effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00692] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00693] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological- based methods, e. g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00694] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00695] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequellae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00696] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00697] Whether combination therapy with a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00698] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist. Liver functions include, but are not limited to ; synthesis of proteins such as serum proteins (e. g. , albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y- glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids ; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs ; a hemodynamic function, including splanchnic and portal hemodynamics ; and the like.

[00699] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00700] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00701] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF- a antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

6) Type II interferon receptor agonist and TNF antagonist in combination therapy to treat liver fibrosis [00702] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering an effective combination of a Type II interferon receptor agonist and a TNF-a antagonist to an individual in need thereof. Of particular interest in many embodiments is treatment of humans.

[00703] The present methods generally involve administering therapeutically effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist. As used herein,"effective amounts"of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective in reducing liver fibrosis or reduce the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00704] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a Type II interferon receptor agonist and a TNF-a antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00705] Whether treatment with a combination of a Type II interferon receptor agonist and a TNF-a antagonist is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long-- term disease progression. See, e. g. , Brunt (2000) Hepatol. 31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00706] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00707] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00708] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J HepatoL 13: 372.

[00709] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00710] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00711] In some embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00712] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00713] In another embodiment, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00714] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00715] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00716] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00717] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequellae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00718] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00719] Whether combination therapy with a Type II interferon receptor agonist and a TNF-a antagonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00720] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids ; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism ; detoxification of exogenous drugs ; a hemodynamic function, including splanchnic and portal hemodynamics ; and the like.

[00721] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00722] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00723] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a Type II interferon receptor agonist and a TNF- a antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

7) Pirfenidone and TNF antagonist in combination therapy to treat liver fibrosis [00724] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering an effective combination of pirfenidone or a pirfenidone analog, and a TNF-a antagonist to an individual in need thereof. Of particular interest in many embodiments is treatment of humans.

[00725] The present methods generally involve administering therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist. As used herein,"effective amounts"of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective in reducing liver fibrosis or reduce the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00726] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00727] Whether treatment with a combination of pirfenidone or a pirfenidone analog, and a TNF-a antagonist is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long- term disease progression. See, e. g., Brunt (2000) Hepatol. 31: 241-246 ; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00728] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes ; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00729] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00730] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) R Hepatol. 13: 372.

[00731] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00732] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00733] In some embodiments, therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00734] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00735] In another embodiment, effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00736] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00737] In another embodiment, therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00738] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00739] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequellae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00740] In another embodiment, therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00741] Whether combination therapy with pirfenidone or a pirfenidone analog, and a TNF-a antagonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00742] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[00743] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00744] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00745] In another embodiment, therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. Therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are also any combined dosage effective to increase a reduced level of a-- serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

8) Type II interferon receptor agonist and TGF-ß antagonist in combination therapy to treat liver fibrosis [00746] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering an effective combination of pirfenidone or a pirfenidone analog, and a TGF-ß antagonist to an individual in need thereof. Of particular interest in many embodiments is treatment of humans.

[00747] The present methods generally involve administering therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-P antagonist. As used herein,"effective amounts"of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00748] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00749] Whether treatment with a combination of a Type II interferon receptor agonist, and a TGF- (3 antagonist is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long- term disease progression. See, e. g., Brunt (2000) Hepatol. 31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy,-a score is assigned.-A number-of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00750] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation) ; bile duct changes; and the Knodell index (scores of-periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00751] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation ; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00752] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13: 372.

[00753] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00754] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00755] In some embodiments, therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00756] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00757] In another embodiment, effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00758] In another embodiment, effective amounts of a Type II interferon receptor agonist, and a TGF-P antagonist are any combined dosage that is effective to slow the deterioration in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the deterioration in the index of liver function that would occur in an untreated individual, or in a placebo-treated individual.

[00759] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00760] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods ;-e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00761] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective to reduce the rate of increase in the serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the increase in the level of the marker that would occur in an untreated individual, or in a placebo- treated individual.

[00762] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00763] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequelae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00764] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00765] Whether combination therapy with a Type II interferon receptor agonist, and a TGF-P antagonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00766] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[00767] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00768] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00769] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-P antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF- ß antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

9) SAPK inhibitors in monotherapy and combination therapy for the treatment of liver fibrosis [00770] In some embodiments, the present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering an effective amount of a SAPK inhibitor to an individual in need thereof. Of particular interest in many embodiments is treatment of humans. In these embodiments, the method generally involves administering an effective amount of an agent that inhibits a stress- activated protein kinase (SAPK), otherwise referred to herein as"a SAPK inhibitor, "e. g. , the agent inhibits enzymatic activity of a SAPK, where the SAPK inhibitor is other than pirfenidone or a pirfenidone analog, and where the SAPK inhibitor is other than a compound of Formula I as set forth in U. S. Patent Publication No. 20030149041.

[00771] In another aspect, the invention provides methods of treating liver fibrosis, the methods generally involving administering an effective amount of a SAPK inhibitor and an effective amount of a Type II interferon receptor agonist to an individual in need thereof. In other embodiments, the methods generally involve administering an effective amount of a SAPK inhibitor, an effective amount of a Type II interferon receptor agonist, and an effective amount of a Type I interferon receptor agonist to an individual in need thereof.

[00772] In another aspect, the invention provides methods of treating liver fibrosis, the methods generally involving administering an effective amount of a SAPK inhibitor and an effective amount of a TNF antagonist (e. g. , etanercept, infliximab, or adalimumab) to an individual in need thereof.

[00773] In another aspect, the invention provides methods of treating liver fibrosis, the methods generally involving administering an effective amount of a SAPK inhibitor and an effective amount of a TGF-p antagonist (e. g. , imatinib mesylate) to an individual in need thereof.

[00774] In another aspect, the invention provides methods of treating liver fibrosis, the methods generally involving administering an effective amount of a SAPK inhibitor and an effective amount of an endothelin receptor antagonist (e. g. , bosentan) to an individual in need thereof.

[00775] The present methods generally involve administering a therapeutically effective amount of a SAPK inhibitor. In some embodiments, a therapeutically effective amount of a SAPK inhibitor is any dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00776] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist. In some embodiments, therapeutically effective amount of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00777] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist. In some embodiments, therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00778] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist. In some embodiments, therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00779] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of a SAPK inhibitor and a TGF-ß antagonist. In some embodiments, therapeutically effective amounts of a SAPK inhibitor and a TGF-P antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis ; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00780] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of a SAPK inhibitor and an endothelin receptor antagonist.

In some embodiments, therapeutically effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis ; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00781] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual an amount of a SAPK inhibitor that is effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00782] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a SAPK inhibitor and a Type II interferon receptor agonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00783] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00784] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a SAPK inhibitor and a TNF antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00785] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a SAPK inhibitor and a TGF-ß antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00786] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a SAPK inhibitor and an endothelin receptor antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00787] Whether treatment with any of the above-described treatment methods is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by"grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long-term disease progression. See, e. g., Brunt (2000) Hepatol. 31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00788] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00789] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score : 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00790] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J HepatoL 13: 372.

[00791] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00792] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00793] In some embodiments, a therapeutically effective amount of a SAPK inhibitor is any dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post- therapy liver biopsies. In particular embodiments, a therapeutically effective amount of a SAPK inhibitor reduces liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00794] In some embodiments, therapeutically effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00795] In some embodiments, therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00796] In some embodiments, therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00797] In some embodiments, therapeutically effective amounts of a SAPK inhibitor and a TGF-P antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a SAPK inhibitor and a TGF-P antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00798] In some embodiments, therapeutically effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a SAPK inhibitor and endothelin receptor antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00799] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00800] In another embodiment, an effective amount of a SAPK inhibitor is any dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00801] In another embodiment, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00802] In another embodiment, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00803] In another embodiment, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00804] In another embodiment, effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00805] In another embodiment, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00806] In another embodiment, an effective amount of a SAPK inhibitor is any dosage that is effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00807] In another embodiment, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00808] In another embodiment, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00809] In another embodiment, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00810] In another embodiment, effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00811] In another embodiment, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00812] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00813] In another embodiment, a therapeutically effective amount of a SAPK inhibitor is any dosage that is effective to reduce a serum level of a marker of liver fibrosis by-at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological- based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00814] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , ELISA, radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00815] In another embodiment, therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological- based methods, e. g. , ELISA, radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00816] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , ELISA, radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00817] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , ELISA, radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00818] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated- individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , ELISA, radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00819] In another embodiment, an effective amount of a SAPK inhibitor is any dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00820] In another embodiment, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00821] In another embodiment, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% j or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00822] In another embodiment, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00823] In another embodiment, effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00824] In another embodiment, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% j at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00825] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00826] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequellae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00827] In another embodiment, a therapeutically effective amount of a SAPK inhibitor is any dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00828] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective in reducing the incidence of (e. g., the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00829] In another embodiment, therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00830] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00831] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a TGF-p antagonist are any combined dosage that is effective in reducing the incidence of (e. g., the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00832] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00833] Whether any of the above-described therapeutic regimens is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00834] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of pirfenidone or a pirfenidone analog, and a TGF- (3 antagonist. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics ; and the like.

[00835] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00836] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00837] In another embodiment, a therapeutically effective amount of a SAPK inhibitor is any dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, a therapeutically effective amount of a SAPK inhibitor is any dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. A therapeutically effective amount of a SAPK inhibitor is also any dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00838] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00839] In another embodiment, therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00840] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. Therapeutically effective amounts of a SAPK inhibitor and a TNF antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00841] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of a SAPK inhibitor and a TGF- (3 antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00842] In another embodiment, therapeutically effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

10) N-acetvl cystine and SAPK inhibitor in combination therapy for treating liver fibrosis [00843] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering effective amounts of NAC and a SAPK inhibitor to an individual in need thereof. Of particular interest in many embodiments is treatment of humans.

[00844] In another aspect, the invention provides methods of treating liver fibrosis, the methods generally involving administering effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist to an individual in need thereof. In other embodiments, the methods generally involve administering an effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist to an individual in need thereof.

[00845] In another aspect, the invention provides methods of treating liver fibrosis, the methods generally involving administering effective amounts of NAC, a SAPK inhibitor and a TNF antagonist (e. g., etanercept, infliximab, or adalimumab) to an individual in need thereof.

[00846] In another aspect, the invention provides methods of treating liver fibrosis, the methods generally involving administering effective amounts of NAC, a-SAPK inhibitor and a TGF-P antagonist (e. g. , imatinib mesylate) to an individual in need thereof.

[00847] In another aspect, the invention provides methods of treating liver fibrosis, the methods generally involving administering effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist (e. g. , bosentan) to an individual in need thereof.

[00848] The present methods generally involve administering therapeutically effective amounts of NAC and a SAPK inhibitor. In some embodiments, therapeutically effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00849] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist. In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00850] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist. In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00851] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist. In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00852] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF-P antagonist. In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis ; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00853] In another aspect, the methods of the invention generally involve administering therapeutically effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist. In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00854] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of NAC and a SAPK inhibitor that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00855] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00856] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00857] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of NAC, a SAPK inhibitor and a TNF antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00858] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of NAC, a SAPK inhibitor and a TGF-ß antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00859] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g. , increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00860] Whether treatment with any of the above-described treatment methods is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by"grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long-term disease progression. See, e. g., Brunt (2000) Hepatol. 31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00861] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis) ; necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00862] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00863] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture ; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J : Hepatol. 13 : 372.

[00864] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00865] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: As B, or C.

[00866] In some embodiments, therapeutically effective amounts of NAC and a SAPK inhibitor are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, a therapeutically effective amount of a SAPK inhibitor reduces liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00867] In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00868] In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post- therapy liver biopsies. In particular embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00869] In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00870] In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF-P antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00871] In some embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of NAC, a SAPK inhibitor and endothelin receptor antagonist reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00872] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00873] In another embodiment, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00874] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00875] In another embodiment, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00876] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00877] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00878] In another embodiment, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00879] In another embodiment, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00880] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00881] In another embodiment, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00882] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00883] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a TGF-ß antagonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00884] In another embodiment, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual.

[00885] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00886] In another embodiment, therapeutically effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo- treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00887] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00888] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological- based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00889] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00890] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00891] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00892] In another embodiment, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo- treated individual.

[00893] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00894] In another embodiment, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00895] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00896] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00897] In another embodiment, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to slow the increase in a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual.

[00898] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00899] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequellae of decompensated liver disease, i. e. , or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00900] In another embodiment, therapeutically effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00901] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00902] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00903] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00904] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF-p antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00905] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00906] Whether any of the above-described therapeutic regimens is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00907] Reduction in liver fibrosis increases liver function. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g. , albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'- nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[00908] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00909] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00910] In another embodiment, therapeutically effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. Therapeutically effective amounts of NAC and a SAPK inhibitor are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00911] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00912] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00913] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00914] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF-p antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of NAC, a SAPK inhibitor and a TGF-P antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

[00915] In another embodiment, therapeutically effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.

Therapeutically effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at-least about 20%, at-least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

11) N-acetyl cysteine and Type II interferon receptor agonist in combination therapy for treating liver fibrosis [00916] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering an effective combination of a Type II interferon receptor agonist and N-acetylcysteine (NAC) to an individual in need thereof. Of particular interest in many embodiments is treatment of humans.

[00917] The present methods generally involve administering therapeutically effective amounts of a Type II interferon receptor agonist and NAC. In some embodiments, "effective amounts" of a Type II interferon receptor agonist and NAC are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis ; and/or that is effective in reducing a parameter associated with liver fibrosis ; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[00918] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of a Type II interferon receptor agonist and NAC that are effective for prophylaxis or therapy of liver fibrosis in the individual, e. g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00919] Whether treatment with a combination of a Type II interferon receptor agonist and NAC is effective in reducing liver fibrosis can be determined by any of a number of well- established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by"grade"as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by"stage"as being reflective of long-term disease progression. See, e. g., Brunt (2000) Hepatol. 31: 241-246 ; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[00920] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation) ; bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis ; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00921] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.

Knodell (1981) Hepatol. 1: 431.

[00922] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal-septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J Hepatol. 13: 372.

[00923] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22: 696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some'portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[00924] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[00925] In some embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre-and post-therapy liver biopsies. In other embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and NAC reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00926] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00927] In another embodiment, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00928] In another embodiment, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the decline in the index of liver function that would occur in an untreated individual, or in a placebo-treated individual.

[00929] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00930] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e. g. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00931] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to slow the rate of increase in the serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the rate of increase in the level of the marker that would occur in an untreated individual, or in a placebo- treated individual.

[00932] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00933] As used herein, a"complication associated with cirrhosis of the liver"refers to a disorder that is a sequelae of decompensated liver disease, i. e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00934] In another embodiment, therapeutically effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective in reducing the incidence of (e. g. , the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00935] Whether combination therapy with a Type II interferon receptor agonist and NAC is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00936] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of a Type II interferon receptor agonist and NAC. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e. g. , albumin, clotting factors, alkaline phosphatase, aminotransferases (e. g. , alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc. ), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism ; detoxification of exogenous drugs ; a hemodynamic function, including splanchnic and portal hemodynamics ; and the like.

[00937] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00938] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins.

The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays.

Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[00939] In another aspect, therapeutically effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. In some of these embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. In other embodiments, therapeutically effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

Renal Fibrosis [00940] Renal fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) components. Overproduction of transforming growth factor-beta (TGF- (3) is believed to underlie tissue fibrosis caused by excess deposition of ECM, resulting in disease. TGF-ß's fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation and enhanced integrin expression that facilitates ECM assembly.

[00941] The present invention provides methods of treating renal fibrosis. In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor. In other embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist; and a tumor necrosis factor (TNF) antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-p) antagonist. In other embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist. Of particular interest in many embodiments is treatment of humans.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat renal fibrosis 2] In some embodiments, subject methods for treating renal fibrosis generally involve administering to an individual having renal fibrosis effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist. As used herein, "effective amounts" of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective in reducing renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

3] In one embodiment, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

4] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6,214, 542.

5] In some embodiments, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[00946] In some embodiments, effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist-are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00947] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

2) Type II interferon receptor agonist, SAPK inhibitor, and third therapeutic agent in combination therapy for treating renal fibrosis [00948] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual having renal fibrosis an effective amount of a Type II interferon receptor agonist, an effective amount of a SAPK inhibitor, and a third therapeutic agent (e. g. , a palliative agent or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent). As used herein, "effective amounts"of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective in reducing renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00949] In one embodiment, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00950] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6, 2-14 ; 542-.-- [00951] In some embodiments, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[00952] In some embodiments, effective amounts of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00953] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to- treat renal fibrosis [00954] The present invention provides methods of treating renal fibrosis. The methods generally involving administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist in combined effective amounts to treat the proliferative disorder. In some embodiments, the Type II interferon receptor agonist is IFN-y.

In some embodiments, the IFN-y is Actimmune human IFN-ylb. In some embodiments, the VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR.

[00955] In some embodiments, "effective amounts"of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00956] In one embodiment, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00957] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6,214, 542.

[00958] In some embodiments, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the baseline level of kidney function in the individual prior to treatment.

[00959] In some embodiments, effective amounts of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00960] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat renal fibrosis [00961] Renal fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) components. Overproduction of transforming growth factor-beta (TGF-ß) is believed to underlie tissue fibrosis caused by excess deposition of ECM, resulting in disease. TGF-ß's fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation and enhanced integrin expression that facilitates ECM assembly.

[00962] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual in need thereof a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, in combined effective amounts to treat the renal fibrosis. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00963] In some embodiments, a subject combination therapy to treat renal fibrosis involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the renal fibrosis. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[00964] In some embodiments, "effective amounts"of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective in reducing renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00965] In one embodiment, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00966] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78 : 511-522; U. S. Patent No : 6,214, 542.

[00967] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the baseline level of kidney function in the individual prior to treatment.

[00968] In some embodiments, effective amounts of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00969] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

[00970] In other embodiments, any of the above-described methods of treating renal fibrosis can be modified to further comprise administering an amount of at least one additional anti- fibrotic agent effective to augment the anti-fibrotic treatment received by the individual. In some of these embodiments, the additional anti-fibrotic agent is selected from a TGF-P antagonist, an endothelin receptor antagonist, and N-acetylcysteine (NAC).

5) Type I or Type III interferon receptor agonist, Type II interferon receptor agonist, and TNF antagonist in combination therapy to treat renal fibrosis [00971] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual having renal fibrosis effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist. As used herein, "effective amounts"of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis ;- and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00972] In one embodiment, effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00973] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6,214, 542.

[00974] In some embodiments, effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[00975] In some embodiments, effective amounts of a Type II interferon receptor agonist, a Type I or III interferon receptor agonist, and a TNF-a antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00976] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

6) Type II interferon receptor agonist and TNF antagonist in combination therapy to treat renal fibrosis [00977] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual having renal fibrosis effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist. As used herein,"effective amounts"of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective in reducing renal-fibrosis ; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00978] In one embodiment, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00979] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6,214, 542.

[00980] In some embodiments, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[00981] In some embodiments, effective amounts of a Type II interferon receptor agonist and a TNF-a antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00982] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

7) Pirfenidone and TNF antagonist in combination therapy to treat renal fibrosis [00983] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual having renal fibrosis effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist. As used herein,"effective amounts"of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00984] In one embodiment, effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00985] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6,214, 542.

[00986] In some embodiments, effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% ; at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[00987] In some embodiments, effective amounts of pirfenidone or a pirfenidone analog, and a TNF-a antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00988] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL) ; creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

8) Type II interferon receptor agonist and TGF-I} antavonist in combination therapy to treat renal fibrosis [00989] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual having renal fibrosis effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist. As used herein,"effective amounts"of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00990] In one embodiment, effective amounts of a Type II interferon receptor agonist, and a TGF- (3 antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00991] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6,214, 542.

[00992] In some embodiments, effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[00993] In some embodiments, effective amounts of a Type II interferon receptor agonist, and a TGF-ß antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00994] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

9) SAPK inhibitors in monotherapy and combination therapy for the treatment of fibrotic disorders [00995] In some embodiments, the present invention provides methods of treating renal fibrosis.

The methods generally involve administering to an individual having renal fibrosis an effective amount of a SAPK inhibitor. In these embodiments, the method generally involves administering an effective amount of an agent that inhibits a stress-activated protein kinase (SAPK), otherwise referred to herein as"a SAPK inhibitor, "e. g. , the agent inhibits enzymatic activity of a SAPK, where the SAPK inhibitor is other than pirfenidone or a pirfenidone analog, and where the SAPK inhibitor is other than a compound of Formula I as set forth in U. S. Patent Publication No. 20030149041.

[00996] In some embodiments, an effective amount of a SAPK inhibitor is any dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00997] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist.

In some embodiments, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00998] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist. In some embodiments, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis ; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[00999] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of a SAPK inhibitor and a TNF antagonist (e. g. , etanercept, infliximab, or adalimumab). In some embodiments, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney : [001000] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of a SAPK inhibitor and a TGF- (3 antagonist (e. g. , imatinib mesylate). In some embodiments, effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[001001] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of a SAPK inhibitor and an endothelin receptor antagonist (e. g. , bosentan). In some embodiments, effective amounts of a SAPK inhibitor and endothelin receptor antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney ; [001002] In another embodiment, an effective amount of a SAPK inhibitor is any dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001003] In another embodiment, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001004] In another embodiment, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001005] In another embodiment, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001006] In another embodiment, effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001007] In another embodiment, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001008] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522 ; U. S. Patent No. 6,214, 542.

[001009] In some embodiments, an effective amount of a SAPK inhibitor is any dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001010] In some embodiments, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001011] In some embodiments, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001012] In some embodiments, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to-treatment.

[001013] In some embodiments, effective amounts of a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001014] In some embodiments, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001015] In some embodiments, an effective amount of a SAPK inhibitor is any dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001016] In some embodiments, effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001017] In some embodiments, effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001018] In some embodiments, effective amounts of a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001019] In some embodiments, effective amounts of a SAPK inhibitor and a TGF-P antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001020] In some embodiments, effective amounts of a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001021] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

10) N-acetyl cysteine and SAPK inhibitor in combination therapy for treating fibrotic disorders [001022] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual having renal fibrosis effective amounts of NAC and a SAPK inhibitor. In some embodiments, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[001023] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist. In some embodiments, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[001024] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist. In some embodiments, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[001025] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of NAC, a SAPK inhibitor and a TNF antagonist (e. g., etanercept, infliximab, or adalimumab). In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[001026] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of NAC, a SAPK inhibitor and a TGF-p antagonist (e. g., imatinib mesylate). In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TGF-p antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[001027] In another aspect, a subject method involves administering to an individual having renal fibrosis effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist (e. g. , bosentan). In some embodiments, effective amounts of NAC, a SAPK inhibitor and endothelin receptor antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis ; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[001028] In another embodiment, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001029] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001030] In another embodiment, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001031] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at-least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001032] In another embodiment, effective amounts of NAC, a SAPK inhibitor and a TGF-p antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001033] In another embodiment, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001034] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6,214, 542.

[001035] In some embodiments, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001036] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001037] In some embodiments, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001038] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001039] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TGF-ß antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001040] In some embodiments, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001041] In some embodiments, effective amounts of NAC and a SAPK inhibitor are any combined dosage that is effective to slow the decline in kidney function by at least about. 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001042] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a Type II interferon receptor agonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001043] In some embodiments, effective amounts of NAC, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001044] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TNF antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001045] In some embodiments, effective amounts of NAC, a SAPK inhibitor and a TGF- (3 antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001046] In some embodiments, effective amounts of NAC, a SAPK inhibitor and an endothelin receptor antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001047] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL) ; and urine protein levels.

11) N-acetvl cystine and Type II interferon receptor agonist in combination therapy for treating fibrotic disorders [001048] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual having renal fibrosis effective amounts of a Type II interferon receptor agonist and NAC. In some embodiments, "effective amounts"of a Type II interferon receptor agonist and NAC are any combined dosage that is effective in reducing renal fibrosis ; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney.

[001049] In other embodiments, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[001050] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e. g. , Masseroli et al.

(1998) Lab. Invest. 78: 511-522; U. S. Patent No. 6,214, 542.

[001051] In some embodiments, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[001052] In some embodiments, effective amounts of a Type II interferon receptor agonist and NAC are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[001053] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels.

Angiogenesis-Mediated Disorders [001054] The present invention provides methods for treating angiogenic disorders. In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor. In other embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist; and a tumor necrosis factor (TNF) antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-ß) antagonist. In other embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist. Of particular interest in many embodiments is treatment of humans.

[001055] A subject method is useful for treating angiogenic disorders, e. g. , any disease characterized by pathological neovascularization. Such disorders include, but are not limited to, solid tumors, hemangiomas, rheumatoid arthritis, atherosclerosis, fibrotic disorders, including idiopathic pulmonary fibrosis (IPF), liver fibrosis, and renal fibrosis; but also include BPH, vascular restenosis, arteriovenous malformations (AVM), retinopathies, including diabetic retinopathy, meningioma, hemangiomas, thyroid hyperplasias (including Grave's disease), neovascular glaucoma, neovascularization associated with corneal injury, neovascularization associated with corneal transplantation, neovascularization associated with corneal graft, psoriasis, angiofibroma, hemophilic joints, hypertrophic scars, osler-weber syndrome, age-related macular degeneration, pyogenic granuloma retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, an inflammatory bowel disease such as, for example, Crohn's disease or ulcerative colitis, and endometriosis.

[001056] Many systems are available for assessing angiogenesis, and any such system can be used to assess whether an agent, an amount of an agent, or a method is effective in reducing angiogenesis. For example, as angiogenesis is required for solid tumor growth, the inhibition of tumor growth in an animal model may be used as an index of the inhibition of angiogenesis.

Angiogenesis may also be assessed in terms of models of wound-healing, in cutaneous or organ wound repair; and in chronic inflammation, e. g. , in diseases such as rheumatoid arthritis, atherosclerosis and idiopathic pulmonary fibrosis (IPF). It may also be assessed by counting vessels in tissue sections, e. g. , following staining for marker molecules, e. g. , CD3H, Factor VIII or PECAM-1.

[001057] Whether angiogenesis is reduced can be determined using any method known in the art, including, e. g. , stimulation of neovascularization into implants impregnated with relaxin; stimulation of blood vessel growth in the cornea or anterior eye chamber; stimulation of endothelial cell proliferation, migration or tube formation in vitro ; and the chick chorioallantoic membrane assay; the hamster cheek pouch assay; the polyvinyl alcohol sponge disk assay. Such assays are well known in the art and have been described in numerous publications, including, e. g., Auerbach et al. ((1991) Pharmac. Ther. 51 : 1-11), and references cited therein.

[001058] A system in widespread use for assessing angiogenesis is the corneal micropocket assay of neovascularization, as may be practiced using rat corneas. This in vivo model is widely accepted as being generally predictive of clinical usefulness. See, e. g. , O'Reilly et. al. (1994) Cell 79 : 315-328, Li et. al. (1991) Invest. Ophthalmol. Vis. Sci. 32 (11): 2898-905; and Miller et. al. (1994) Am. R Pathol. 145 (3): 574-84.

1) Type 11 interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat anviovenesis-mediated disorders [001059] In some embodiments, subject methods for treating angiogenesis-mediated disorders generally involve administering effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist to an individual in need thereof.

[001060] In a subject method of treating an angiogenic disorder, "effective amounts"of a Type II interferon receptor agonist and a Type I interferon receptor agonist are any combined dosage that is angiostatic, e. g. , an amount that reduces angiogenesis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared with the level of angiogenesis in the absence of treatment with dual IFN receptor agonist therapy.

2) Type II interferon receptor agonist, SAPK inhibitor, and third therapeutic avent in combination therapy for treating angiogenesis-mediated disorders [001061] The present invention provides methods for treating angiogenic disorders. The methods generally involve administering to an individual in need thereof (e. g. , an individual having an angiogenic disorder) an effective amount of a Type II interferon receptor agonist, an effective amount of a SAPK inhibitor, and a third therapeutic agent (e. g. , a palliative agent or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent).

[001062] In a subject method of treating an angiogenic disorder, "effective amounts"of a Type II interferon receptor agonist and a SAPK inhibitor are any combined dosage that is angiostatic, e. g., an amount that reduces angiogenesis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared with the level of angiogenesis in the absence of treatment with the subject combination therapy.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat ansiosenesis-mediated disorders [001063] The present invention provides methods for treating angiogenic disorders. The methods generally involving administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist in combined effective amounts to treat the angiogenic disorder. In some embodiments, the Type II interferon receptor agonist is IFN-Y.

In some embodiments, the IFN-y is ActimmuneOO human IFN-ylb. In some embodiments, the VEGF antagonist is selected from a VEGF receptor (VEGFR) tyrosine kinase inhibitor, an antibody specific for VEGF, an antibody specific for a VEGFR, a soluble VEGFR, a ribozyme that inhibits a VEGFR, an antisense that inhibits a VEGFR, and an siRNA that inhibits a VEGFR. Of particular interest in many embodiments is the treatment of humans. In some embodiments, a subject method further comprises administering one or more of a Type I interferon receptor agonist, a TNF antagonist, and a SAPK inhibitor.

[001064] In some of the subject methods of treating an angiogenic disorder, "effective amounts" of a Type II interferon receptor agonist and a VEGF antagonist are any combined dosage that is angiostatic, e. g. , an amount that reduces angiogenesis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared with the level of angiogenesis in the absence of treatment with the subject combination therapy.

[001065] Many systems are available for assessing angiogenesis. For example, as angiogenesis is required for solid tumor growth, the inhibition of tumor growth in an animal model may be used as an index of the inhibition of angiogenesis. Angiogenesis may also be assessed in terms of models of wound-healing, in cutaneous or organ wound repair ; and in chronic inflammation, e. g. , in diseases such as rheumatoid arthritis, atherosclerosis and idiopathic pulmonary fibrosis (IPF). It may also be assessed by counting vessels in tissue sections, e. g. , following staining for marker molecules, e. g. , CD3H, Factor VIII or PECAM-1.

[001066] Whether angiogenesis is reduced can be determined using any method known in the art, including, e. g. , stimulation of neovascularization into implants impregnated with relaxin ; stimulation of blood vessel growth in the cornea or anterior eye chamber; stimulation of endothelial cell proliferation, migration or tube formation in vitro ; and the chick chorioallantoic membrane assay; the hamster cheek pouch assay; the polyvinyl alcohol sponge disk assay. Such assays are well known in the art and have been described in numerous publications, including, e. g. , Auerbach et al. ( (1991) Pharmac. Ther. 51: 1-11), and references cited therein.

[001067] A system in widespread use for assessing angiogenesis is the corneal micropocket assay of neovascularization, as may be practiced using rat corneas. This in vivo model is widely accepted as being generally predictive of clinical usefulness. See, e. g. , O'Reilly et. al. (1994) Cell 79 : 315-328, Li et. al. (1991) Invest. Ophthalmol. Vis. Sci. 32 (11): 2898-905 ; and Miller et. al. (1994) Am. J Pathol. 145 (3) : 574-84.

[001068] A subject method is useful for treating angiogenic disorders, e. g. , any disease characterized by pathological neovascularization. Such disorders include, but are not limited to, solid tumors, hemangiomas, rheumatoid arthritis, atherosclerosis, fibrotic disorders, including idiopathic pulmonary fibrosis (IPF), liver fibrosis, and renal fibrosis; but also include BPH, vascular restenosis, arteriovenous malformations (AVM), retinopathies, including diabetic retinopathy, meningioma, hemangiomas, thyroid hyperplasias (including Grave's disease), neovascular glaucoma, neovascularization associated with corneal injury, neovascularization associated with corneal transplantation, neovascularization associated with corneal graft, psoriasis, angiofibroma, hemophilic joints, hypertrophic scars, osler-weber syndrome, age-related macular degeneration, pyogenic granuloma retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, an inflammatory bowel disease such as, for example, Crohn's disease or ulcerative colitis, and endometriosis.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat angiogenesis-mediated disorders [001069] The present invention provides methods for treating angiogenic disorders. The methods generally involve administering to an individual in need thereof a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, in combined effective amounts to treat the angiogenesis-mediated disorder. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g.,-IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[001070] In some embodiments, a subject combination therapy to treat an angiogenesis-mediated disorder involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the angiogenesis-mediated disorder. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[001071] In some embodiments of the subject method of treating an angiogenic disorder, "effective amounts"of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are any combined dosage that is angiostatic, e. g. , an amount that reduces angiogenesis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared with the level of angiogenesis in the absence of treatment with the subject combination therapy.

[001072] Many systems are available for assessing angiogenesis. For example, as angiogenesis is required for solid tumor growth, the inhibition of tumor growth in an animal model may be used as an index of the inhibition of angiogenesis. Angiogenesis may also be assessed in terms of models of wound-healing, in cutaneous or organ wound repair; and in chronic inflammation, e. g. , in diseases such as rheumatoid arthritis, atherosclerosis and idiopathic pulmonary fibrosis (IPF). It may also be assessed by counting vessels in tissue sections, e. g. , following staining for marker molecules, e. g. , CD3H, Factor VIII or PECAM-1.

[001073] Whether angiogenesis is reduced can be determined using any method known in the art, including, e. g. , stimulation of neovascularization into implants impregnated with relaxin; stimulation of blood vessel growth in the cornea or anterior eye chamber; stimulation of endothelial cell proliferation, migration or tube formation in vitro ; and the chick chorioallantoic membrane assay; the hamster cheek pouch assay; the polyvinyl alcohol sponge disk assay. Such assays are well known in the art and have been described in numerous publications, including, e. g., Auerbach et al. ( (1991) Pharmac. Ther. 51 : 1-11), and references cited therein.

[001074] A system in widespread use for assessing angiogenesis is the corneal micropocket assay of neovascularization, as may be practiced using rat corneas. This in vivo model is widely accepted as being generally predictive of clinical usefulness. See, e. g. , O'Reilly et. al. (1994) Cell 79: 315-328, Li et. al. (1991) Invest. Ophthalmol. Vis. Sci. 32 (11): 2898-905 ; and Miller et. al. (1994) Am. J Pathol. 145 (3): 574-84.

[001075] A subject method is useful for treating angiogenic disorders, e. g. , any disease characterized by pathological neovascularization. Such disorders include, but are not limited to, solid tumors, hemangiomas, rheumatoid arthritis, atherosclerosis, fibrotic disorders, including idiopathic pulmonary fibrosis (IPF), liver fibrosis, and renal fibrosis; but also include BPH, vascular restenosis, arteriovenous malformations (AVM), retinopathies, including diabetic retinopathy, meningioma, hemangiomas, thyroid hyperplasias (including Grave's disease), neovascular glaucoma, neovascularization associated with corneal injury, neovascularization associated with corneal transplantation, neovascularization associated with corneal graft, psoriasis, angiofibroma, hemophilic joints, hypertrophic scars, osler-weber syndrome, age-related macular degeneration, pyogenic granuloma retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, an inflammatory bowel disease such as, for example, Crohn's disease or ulcerative colitis, and endometriosis.

THERAPEUTIC AGENTS Type I interferon receptor arsonists [001076] In any of the above-described methods, in some embodiments a Type I interferon receptor agonist is administered. Type I interferon receptor agonists include an IFN-a ; an IFN- p ; an IFN-tau; an IFN-co ; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists.

Interferon-Alpha [001077] Any known IFN-a can be used in the instant invention. The term"interferon-alpha"as used herein refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response. The term"IFN-a"includes naturally occurring IFN-a ; synthetic IFN-a ; derivatized IFN-a (e. g. , PEGylated IFN-a, glycosylated IFN-a, and the like); and analogs of naturally occurring or synthetic IFN-a ; essentially any IFN-a that has antiviral properties, as described for naturally occurring IFN-a.

[001078] Suitable alpha interferons include, but are not limited to, naturally-occurring IFN-a (including, but not limited to, naturally occurring IFN-a2a, IFN-a2b); recombinant interferon alpha-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, N. J.; recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N. J.; recombinant interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical ; Inc. , Ridgefield, Conn.; interferon alpha- nl, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-nl (INS) available from the Glaxo-Wellcome Ltd., London, Great Britain; and interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co. , Norwalk, Conn. , under the Alferon Tradename.

[001079] The term"IFN-a"also encompasses consensus IFN-a. Consensus IFN-a (also referred to as"CIFN"and"IFN-con"and"consensus interferon") encompasses but is not limited to the amino acid sequences designated IFN-conl, IFN-con2 and IFN-con3 which are disclosed in U. S. Pat. Nos. 4,695, 623 and 4, 897, 471; and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (e. g., Infergen@, InterMune, Inc. , Brisbane, Calif.). IFN-conl is the consensus interferon agent in the Infergen alfacon-1 product. The Infergen consensus interferon product is referred to herein by its brand name (Infergen@) or by its generic name (interferon alfacon-1). DNA sequences encoding IFN-con may be synthesized as described in the aforementioned patents or other standard methods. Use of CIFN is of particular interest.

[001080] Also suitable for use in the present invention are fusion polypeptides comprising an IFN-a and a heterologous polypeptide. Suitable IFN-a fusion polypeptides include, but are not limited to, Albuieron-alpha (a fusion product of human albumin and IFN-a ; Human Genome Sciences; see, e. g. , Osborn et al. (2002) J ; Pharmacol. Exp. Therap. 303: 540-548). Also suitable for use in the present invention are gene-shuffled forms of IFN-a. See. , e. g. , Masci et al. (2003) Curr. Oncol. Rep. 5: 108-113.

PEGylated Interferon-Alpha [001081] The term"IFN-a"also encompasses derivatives of IFN-a that are derivatized (e. g. , are chemically modified) to alter certain properties such as serum half-life. As such, the term "IFN-a"includes glycosylated IFN-a ; IFN-a derivatized with polyethylene glycol ("PEGylated IFN-a"); and the like. PEGylated IFN-a, and methods for making same, is discussed in, e. g., U. S. Patent Nos. 5,382, 657; 5,981, 709; and 5,951, 974. PEGylated IFN-a encompasses conjugates of PEG and any of the above-described IFN-a molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, N. J.), interferon alpha 2b (Intron, Schering-Plough, Madison, N. J. ), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen (g), InterMune, Inc. , Brisbane, Calif.).

[001082] Any of the above-mentioned IFN-a polypeptides can be modified with one or more polyethylene glycol moieties, i. e. , PEGylated. The PEG molecule of a PEGylated IFN-a polypeptide is conjugated to one or more amino acid side chains of the IFN-a polypeptide. In some embodiments, the PEGylated IFN-a contains a PEG moiety on only one amino acid. In other embodiments, the PEGylated IFN-a contains a PEG moiety on two or more amino acids, e. g. , the IFN-a contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.

[001083] IFN-a may be coupled directly to PEG (i. e. , without a linking group) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.

[001084] In some embodiments, the PEGylated IFN-a is PEGylated at or near the amino terminus (N-terminus) of the IFN-a polypeptide, e. g. , the PEG moiety is conjugated to the IFN-a polypeptide at one or more amino acid residues from amino acid 1 through amino acid 4, or from amino acid 5 through about 10. In other embodiments, the PEGylated IFN-a is PEGylated at one or more amino acid residues from about 10 to about 28. In other embodiments, the PEGylated IFN-a is PEGylated at or near the carboxyl terminus (C- terminus) of the IFN-a polypeptide, e. g. , at one or more residues from amino acids 156-166, or from amino acids 150 to 155. In other embodiments, the PEGylated IFN-a is PEGylated at one or more amino acid residues at one or more residues from amino acids 100-114.

[001085] The polyethylene glycol derivatization of amino acid residues at or near the receptor- binding and/or active site domains of the IFN-a protein can disrupt the functioning of these domains. In certain embodiments of the invention, amino acids at which PEGylation is to be avoided include amino acid residues from amino acid 30 to amino acid 40; and amino acid residues from amino acid 113 to amino acid 149.

[001086] In some embodiments, PEG is attached to IFN-a via a linking group. The linking group is any biocompatible linking group, where"biocompatible"indicates that the compound or group is non-toxic and may be utilized in vitro or in vivo without causing injury, sickness, disease, or death. PEG can be bonded to the linking group, for example, via an ether bond, an ester bond, a thiol bond or an amide bond. Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS) ), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI) ), a nitro phenyl group (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC) ), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteine group, a histidine group or a primary amine.

[001087] Methods for making succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) ester-activated PEGs are described in U. S. Pat. No. 5,672, 662 (Harris, et al. ) and WO 97/03106.

[001088] Methods for attaching a PEG to an IFN-a polypeptide are known in the art, and any known method can be used. See, for example, by Park et al, Anticancer Res. , 1: 373-376 (1981) ; Zaplipsky and Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed. , Plenum Press, NY, Chapter 21 (1992); U. S. Patent No.

5,985, 265; U. S. Pat. No. 5,672, 662 (Harris, et al. ) and WO 97/03106.

[001089] Pegylated IFN-a, and methods for making same, is discussed in, e. g. , U. S. Patent Nos.

5,382, 657; 5,981, 709; 5,985, 265; and 5,951, 974. Pegylated IFN-a encompasses conjugates of PEG and any of the above-described IFN-a molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, N. J. ), where PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, N. J. ), where PEGylated Intron is known as PEG-Intron (Schering- Plough); interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen@, InterMune, Inc. , Brisbane, Calif. ), where PEGylated Infergen is referred to as PEG-Infergen.

[001090] In many embodiments, the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-a polypeptide. Methods of modifying polypeptides with monomethoxy PEG via reductive alkylation are known in the art. See, e. g. , Chamow et al.

(1994) Bioconj. Chem. 5: 133-140.

[001091] In one non-limiting example, PEG is linked to IFN-a via an SPA linking group. SPA esters of PEG, and methods for making same, are described in U. S. Patent No. 5,672, 662. SPA linkages provide for linkage to free amine groups on the IFN-a polypeptide.

[001092] For example, a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN-a polypeptide. Such a bond can be formed, e. g., by condensation of an a-methoxy, omega propanoic acid activated ester of PEG (mPEGspa).

[001093] As one non-limiting example, one monopegylated CIFN conjugate preferred for use herein has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from lys31, lys50, lysl, lys84, lys121, lys122, lys134, lys135, and lys165, and the amide bond is formed by condensation of an α- methoxy, omega propanoic acid activated ester of PEG.

Polyethylene glycol [001094] Polyethylene glycol suitable for conjugation to an IFN-a polypeptide is soluble in water at room temperature, and has the general formula R (O-CH2-CH2) nO-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons.

[001095] In many embodiments, PEG has at least one hydroxyl group, e. g. , a terminal hydroxyl group, which hydroxyl group is modified to generate a functional group that is reactive with an amino group, e. g. , an epsilon amino group of a lysine residue, a free amino group at the N- terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.

[001096] In other embodiments, PEG is derivatized so that it is reactive with free carboxyl groups in the IFN-a polypeptide, e. g. , the free carboxyl group at the carboxyl terminus of the IFN-a polypeptide. Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN-a include, but are not limited to PEG-amine, and hydrazine derivatives of PEG (e. g., PEG-NH-NH2).

[001097] In other embodiments, PEG is derivatized such that it comprises a terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives. Because of the reactive nature of the thio acid, selectivity of certain amino groups over others is achieved. For example, -SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH conditions such that the s-amino groups in lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions under suitable pH conditions may make some of the accessible lysine residues to react with selectivity.

[001098] In other embodiments, the PEG comprises a reactive ester such as an N-hydroxy succinimidate at the end of the PEG chain. Such an N-hydroxysuccinimidate-containing PEG molecule reacts with select amino groups at particular pH conditions such as neutral 6.5-7. 5.

For example, the N-terminal amino groups may be selectively modified under neutral pH conditions. However, if the reactivity of the reagent were extreme, accessible-NH2 groups of lysine may also react.

[001099] The PEG can be conjugated directly to the IFN-a polypeptide, or through a linker. In some embodiments, a linker is added to the IFN-a polypeptide, forming a linker-modified IFN- a polypeptide. Such linkers provide various functionalities, e. g. , reactive groups such sulfhydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN-a polypeptide.

[001100] In some embodiments, the PEG conjugated to the IFN-a polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-a polypeptide is branched. Branched PEG derivatives such as those described in U. S. Pat. No. 5,643, 575, "star-PEG's"and multi-armed PEG's such as those described in Shearwater Polymers, Inc. catalog"Polyethylene Glycol Derivatives 1997-1998. "Star PEGs are described in the art including, e. g., in U. S. Patent No.

6,046, 305.

[001101] PEG having a molecular weight in a range of from about 2 kDa to about 100 kDa, is generally used, where the term"about, "in the context of PEG, indicates that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight. For example, PEG suitable for conjugation to IFN-a has a molecular weight of from about 2 kDa to about 5 kDa, from about 5 kDa to about 10 kDa, from about 10 kDa to about 15 kDa, from about 15 kDa to about 20 kDa, from about 20 kDa to about 25 kDa, from about 25 kDa to about 30 kDa, from about 30 kDa to about 40 kDa, from about 40 kDa to about 50 kDa, from about 50 kDa to about 60 kDa, from about 60 kDa to about 70 kDa, from about 70 kDa to about 80 kDa, from about 80 kDa to about 90 kDa, or from about 90 kDa to about 100 kDa.

Preparing PEG-IFN-a conjugates [001102] As discussed above, the PEG moiety can be attached, directly or via a linker, to an amino acid residue at or near the N-terminus, internally, or at or near the C-terminus of the IFN-a polypeptide. Conjugation can be carried out in solution or in the solid phase.

N-terminal linkage [001103] Methods for attaching a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-a polypeptide are known in the art. See, e. g. , U. S. Patent No. 5,985, 265.

[001104] In some embodiments, known methods for selectively obtaining an N-terminally chemically modified IFN-a are used. For example, a method of protein modification by reductive alkylation that exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available for derivatization in a particular protein can be used. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved. The reaction is performed at pH that allows one to take advantage of the pKa differences between the s- amino groups of the lysine residues and that of the a-amino group of the N-tenninal residue of the protein. By such selective derivatization attachment of a PEG moiety to the IFN-a is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of the IFN-a and no significant modification of other reactive groups, such as the lysine side chain amino groups, occurs.

C-terminal linkage [001105] N-terminal-specific coupling procedures such as described in U. S. Patent No.

5,985, 265 provide predominantly monoPEGylated products. However, the purification procedures aimed at removing the excess reagents and minor multiply PEGylated products remove the N-terminal blocked polypeptides. In terms of therapy, such processes lead to significant increases in manufacturing costs. For example, examination of the structure of the well-characterized Infergen Alfacon-1 CIFN polypeptide amino acid sequence reveals that the clipping is approximate 5% at the carboxyl terminus and thus there is only one major C- terminal sequence. Thus, in some embodiments, N-terminally PEGylated IFN-a is not used; instead, the IFN-a polypeptide is C-terminally PEGylated.

[001106] An effective synthetic as well as therapeutic approach to obtain mono PEGylated Infergen product is therefore envisioned as follows: [001107] A PEG reagent that is selective for the C-terminal can be prepared with or without spacers. For example, polyethylene glycol modified as methyl ether at one end and having an amino function at the other end may be used as the starting material.

[001108] Preparing or obtaining a water-soluble carbodiimide as the condensing agent can be carried out. Coupling IFN-a (e. g., Infergen Alfacon-1 CIFN or consensus interferon) with a water-soluble carbodiimide as the condensing reagent is generally carried out in aqueous medium with a suitable buffer system at an optimal pH to effect the amide linkage. A high molecular weight PEG can be added to the protein covalently to increase the molecular weight.

[001109] The reagents selected will depend on process optimization studies. A non-limiting example of a suitable reagent is EDAC or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide.

The water solubility of EDAC allows for direct addition to a reaction without the need for prior organic solvent dissolution. Excess reagent and the isourea formed as the by-product of the cross-linking reaction are both water-soluble and may easily be removed by dialysis or gel filtration. A concentrated solution of EDAC in water is prepared to facilitate the addition of a small molar amount to the reaction. The stock solution is prepared and used immediately in view of the water labile nature of the reagent. Most of the synthetic protocols in literature suggest the optimal reaction medium to be in pH range between 4.7 and 6.0. However the condensation reactions do proceed without significant losses in yields up to pH 7.5. Water may be used as solvent. In view of the contemplated use of Infergen, preferably the medium will be 2- (N-morpholino) ethane sulfonic acid buffer pre-titrated to pH between 4.7 and 6.0. However, 0. 1M phosphate in the pH 7-7.5 may also be used in view of the fact that the product is in the same buffer. The ratio of PEG amine to the IFN-a molecule is optimized such that the C- terminal carboxyl residue (s) are selectively PEGylated to yield monoPEGylated derivative (s).

[001110] Even though the use of PEG amine has been mentioned above by name or structure, such derivatives are meant to be exemplary only, and other groups such as hydrazine derivatives as in PEG-NH-NH2 which will also condense with the carboxyl group of the IFN-a protein, can also be used. In addition to aqueous phase, the reactions can also be conducted on solid phase. Polyethylene glycol can be selected from list of compounds of molecular weight ranging from 300-40000. The choice of the various polyethylene glycols will also be dictated by the coupling efficiency and the biological performance of the purified derivative in vitro and in vivo i. e. , circulation times, anti-fibrotic or anti-cancer activities etc.

[001111] Additionally, suitable spacers can be added to the C-terminal of the protein. The spacers may have reactive groups such as SH, NH2 or COOH to couple with appropriate PEG reagent to provide the high molecular weight IFN-a derivatives. A combined solid/solution phase methodology can be devised for the preparation of C-terminal pegylated interferons. For example, the C-terminus of IFN-a is extended on a solid phase using a Gly-Gly-Cys-NH2 spacer and then monopegylated in solution using activated dithiopyridyl-PEG reagent of appropriate molecular weights. Since the coupling at the C-terminus is independent of the blocking at the N-terminus, the envisioned processes and products will be beneficial with respect to cost (a third of the protein is not wasted as in N-terminal PEGylation methods) and contribute to the economy of the therapy to the disorders of the invention.

[001112] There may be a more reactive carboxyl group of amino acid residues elsewhere in the molecule to react with the PEG reagent and lead to monoPEGylation at that site or lead to multiple PEGylations in addition to the-COOH group at the C-terminus of the IFN-a. It is envisioned that these reactions will be minimal at best owing to the steric freedom at the C- terminal end of the molecule and the steric hindrance imposed by the carbodiimides and the PEG reagents such as in branched chain molecules. It is therefore the preferred mode of PEG modification for Infergen and similar such proteins, native or expressed in a host system, which may have blocked N-termini to varying degrees to improve efficiencies and maintain higher in vivo biological activity.

[001113] Another method of achieving C-terminal PEGylation is as follows. Selectivity of C- terminal PEGylation is achieved with a sterically hindered reagent that excludes reactions at carboxyl residues either buried in the helices or internally in IFN-a. For example, one such reagent could be a branched chain PEG-40kd in molecular weight and this agent could be synthesized as follows: OH3C- (CH2CH20) n-CH2CH2NH2 + Glutamic Acid i. e. , HOCO- CH2CH2CH (NH2) -COOH is condensed with a suitable agent e. g. , dicyclohexyl carbodiimide or water-soluble EDC to provide the branched chain PEG agent OH3C- (CH2CH20)"- CH2CH2NHCOCH (NH2) CH20CH3- (CH2CH20)"-CH2CH2NHCOCH2.

[001114] This reagent can be used in excess to couple the amino group with the free and flexible carboxyl group of IFN-a to form the peptide bond.

[001115] If desired, PEGylated IFN-a is separated from unPEGylated IFN-a using any known method, including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. For example, where the PEG-IFN-a conjugate is a monoPEGylated IFN-a, the products are first separated by ion exchange chromatography to obtain material having a charge characteristic of monoPEGylated material (other multi- PEGylated material having the same apparent charge may be present), and then the monoPEGylated materials are separated using size exclusion chromatography.

MonoPEG (30 kD, linear)-ylated IFN-a [001116] PEGylated IFN-a that is suitable for use in the present invention includes a monopegylated consensus interferon (CIFN) molecule comprised of a single CIFN polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly linked through a stable covalent linkage to either the N-terminal residue in the CIFN polypeptide or a lysine residue in the CIFN polypeptide. In some embodiments, the monoPEG (30 kD, linear)-ylated IFN-a is monoPEG (30 kD, linear) -ylated consensus IFN-a.

[001117] In some embodiments, the PEG moiety is linked to either the alpha-amino group of the N-terminal residue in the CIFN polypeptide or the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon- amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide, thereby forming a hydrolytically stable linkage between the PEG moiety and the CIFN polypeptide.

[001118] In some embodiments, the PEG moiety is linked to the N-terminal residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. hi still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N-terminal residue of the CIFN polypeptide.

[001119] In some embodiments, the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon- amino group of the lysine residue in the CIFN polypeptide.

[001120] In some embodiments, the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide.

[001121] In some embodiments, the PEG moiety is linked to a lysine chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys, lys, lys, lys84, lYS121, lysl22, lysl34, lysl35 and lysl65 of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.

[001122] In some embodiments, the PEG moiety is linked to a lysine chosen from lys, lys, lysl35, and lys 165 of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys121, lys134, lys135, and lys165 of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon- amino group of the chosen lysine residue in the CIFN polypeptide.

[001123] In connection with the above-described monopegylated CIFN molecules, the invention contemplates embodiments of each such molecule where the CIFN polypeptide is chosen from interferon alpha-conl, interferon alpha-con2, and interferon alpha-cons, the amino acid sequences of which CIFN polypeptides are disclosed in U. S. Pat. No. 4,695, 623.

Populations of IFN-a [001124] In addition, any of the methods of the invention can employ a PEGylated IFN-a composition that comprises a population of monopegylated IFNa molecules, where the population consists of one or more species of monopegylated IFNa molecules as described above. The subject composition comprises a population of modified IFN-a polypeptides, each with a single PEG molecule linked to a single amino acid residue of the polypeptide.

[001125] In some of these embodiments, the population comprises a mixture of a first IFN-a polypeptide linked to a PEG molecule at a first amino acid residue; and at least a second IFN-a polypeptide linked to a PEG molecule at a second amino acid residue, wherein the first and second IFN-a polypeptides are the same or different, and wherein the location of the first amino acid residue in the amino acid sequence of the first IFN-a polypeptide is not the same as the location of the second amino acid residue in the second IFN-a polypeptide. As one non- limiting example, a subject method can use a composition that comprises a population of PEG- modified IFN-a polypeptides, the population comprising an IFN-a polypeptide linked at its amino terminus to a linear PEG molecule; and an IFN-a polypeptide linked to a linear PEG molecule at a lysine residue.

[001126] Generally, a given modified IFN-a species represents from about 0.5% to about 99.5% of the total population of monopegylated IFNa polypeptide molecules in a population, e. g, a given modified IFN-a species represents about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5% of the total population of monopegylated IFN-a polypeptide molecules in a population. In some embodiments, a subject method can use a composition that comprises a population of monopegylated IFN-a polypeptides, which population comprises at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, IFN-a polypeptides linked to PEG at the same site, e. g. , at the N-terminal amino acid.

[001127] In particular embodiments of interest, a subject method can use a composition that comprises a population of monopegylated CIFN molecules, the population consisting of one or more species of molecules, where each species of molecules is characterized by a single CIFN polypeptide linked, directly or indirectly in a covalent linkage, to a single linear PEG moiety of about 30 kD in molecular weight, and where the linkage is to either a lysine residue in the CIFN polypeptide, or the N-terminal amino acid residue of the CIFN polypeptide.

[001128] The amino acid residue to which the PEG is attached is in many embodiments the N- terminal amino acid residue. In other embodiments, the PEG moiety is attached (directly or via a linker) to a surface-exposed lysine residue. In additional embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys31, lys50, lys7l, lys84, lysl2l, lysl22, lysl34, lysl35, and lysl65 of the CIFN polypeptide. In further embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys121, lys134, ys, and lys of the CIFN polypeptide.

[001129] As an example, a subject method can use a composition that comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject method can use a composition that further comprises at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[001130] As another example, a subject method can use a composition that comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface- exposed lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject method can use a composition that further comprises at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[001131] As another example, a subject method can use a composition that comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys, lys50, lys7l, lys84, lysl2l lysl22 lysl34 lysl35 d 1 165 CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject method can use a composition that further comprises a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide.

A subject method can use a composition that further comprises at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[001132] As another example, a subject method can use a composition that comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one oflys, lys, lys, and lys in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject method can use a composition that can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lysl2l, lysl34, lysl35, and lysl65 in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A subject method can use a composition that further comprises at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lysl2l, lysl34, lysl35, and lYS165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[001133] As another non-limiting example, a subject method can use a composition that comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first lysine is located in a-position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. A subject method can use a composition that further comprises at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[001134] As another non-limiting example, a subject method can use a composition that comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys31, lys50, lysl, lys84, lys121, lys122, lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys31, lys50, lys71, lys84, lys121, lys122 lys134, lys135, and lys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[001135] As another non-limiting example, a subject method can use a composition that comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys121, lys134, lys135, and lys165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys121, lys134, lysis, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lysl2l, lysl34, lysl35, and lysl65, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[001136] As another non-limiting example, a subject method can use a composition that comprises a monopegylated population of CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second surface- exposed lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first surface-exposed lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second surface-exposed lysine residue in the amino acid sequence of the second CIFN polypeptide. A subject method can use a composition that further comprises at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[001137] In connection with each of the above-described populations of monopegylated CIFN molecules, the invention contemplates embodiments where the molecules in each such population comprise a CIFN polypeptide chosen from interferon alpha-conl, interferon alpha- con2, and interferon alpha-con3.

[001138] The invention further features a product that is produced by the process of reacting CIFN polypeptide with a succinimidyl ester of alpha-methoxy, omega-propionylpoly (ethylene glycol) (mPEGspa) that is linear and about 30 kD in molecular weight, where the reactants are initially present at a molar ratio of about 1: 1 to about 1: 5 CIFN: mPEGspa, and where the reaction is conducted at a pH of about 7 to about 9, followed by recovery of the monopegylated CIFN product of the reaction. In one embodiment, the reactants are initially present at a molar ratio of about 1: 3 CIFN: mPEGspa and the reaction is conducted at a pH of about 8. In another embodiment where the product of the invention is generated by a scaled-up procedure needed for toxicological and clinical investigations, the reactants are initially present in a molar ratio of 1: 2 CIFN: mPEGspa and the reaction is conducted at a pH of about 8.0.

[001139] In connection with the above-described product-by-process, the invention contemplates embodiments where the CIFN reactant is chosen from interferon alpha-conl, interferon alpha- con2, and interferon alpha-con3.

IFN-P [001140] The term interferon-beta ("IFN-ß") includes IFN-R polypeptides that are naturally occurring; non-naturally-occurring IFN-R polypeptides; and analogs and variants of naturally occurring or non-naturally occurring IFN-R that retain antiviral activity of a parent naturally- occurring or non-naturally occurring IFN-ß.

[001141] Any of a variety of beta interferons can be used in a subject method. Suitable beta interferons include, but are not limited to, naturally-occurring IFN-p ; IFN-ßla, e. g., Avonexg (Biogen, Inc. ), and Rebif (Serono, SA); IFN-ßlb (Betaseron (g) ; Berlex); and the like.

[001142] The IFN-P formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN- (3.

[001143] IFN-R polypeptides can be produced by any known method. DNA sequences encoding IFN- (3 may be synthesized using standard methods. In many embodiments, IFN-p polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e. g., E. coli, or in eukaryotic host cells (e. g. , yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-R is"recombinant IFN- Where the host cell is a bacterial host cell, the IFN-R is modified to comprise an N- terminal methionine.

[001144] It is to be understood that IFN-ß as described herein may comprise one or more modified amino acid residues, e. g. , glycosylations, chemical modifications, and the like.

IFN-tau [001145] The term interferon-tau includes IFN-tau polypeptides that are naturally occurring; non- naturally-occurring IFN-tau polypeptides; and analogs and variants of naturally occurring or non-naturally occurring IFN-tau that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-tau. Suitable tau interferons include, but are not limited to, naturally occurring IFN-tau; Tauferon (Pepgen Corp. ); and the like.- [001146] IFN-tau may comprise an amino acid sequence as set forth in any one of GenBank AccessionNos. P15696 ; P56828; P56832; P56829; P56831 ; Q29429; Q28595 ; Q28594; S08072 ; Q08071 ; Q08070; Q08053 ; P56830; P28169; P28172; and P28171. The sequence of any known IFN-tau polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i. e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine) ; (lysine, arginine) ; or (phenylalanine, tyrosine).

[001147] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e. g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e. g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e. g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e. g. phosphotyrosine, phosphoserine, or phosphothreonine.

[001148] The IFN-tau formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-tau.

[001149] IFN-tau polypeptides can be produced by any known method. DNA sequences encoding IFN-tau may be synthesized using standard methods. In many embodiments, IFN-tau polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e. g. , E. coli, or in eukaryotic host cells (e. g. , yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-tau is"recombinant IFN-tau. "Where the host cell is a bacterial host cell, the IFN-tau is modified to comprise an N-terminal methionine.

[001150] It is to be understood that IFN-tau as described herein may comprise one or more modified amino acid residues, e. g. , glycosylations, chemical modifications, and the like.

IFN-co [001151] The term interferon-omega ("IFN-E3") includes IFN--w polypeptides that-are naturally occurring; non-naturally-occurring IFN-m polypeptides; and analogs and variants of naturally occurring or non-naturally occurring IFN-that retain effective therapeutic activity of a parent naturally-occurring or non-naturally occurring IFN-co.

[001152] Any known omega interferon can be used in a subject method. Suitable IFN-m include, but are not limited to, naturally-occurring IFN-co ; recombinant IFN-co, e. g. , Biomed 510 (BioMedicines); and the like.

[001153] IFN- may comprise an amino acid sequence as set forth in GenBank Accession No.

NP002168 ; or AAA70091. The sequence of any known IFN-co polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i. e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine) ; (lysine, arginine); or (phenylalanine, tyrosine).

[001154] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e. g. , acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e. g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e. g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e. g. phosphotyrosine, phosphoserine, or phosphothreonine.

[001155] The IFN-o formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-0).

[001156] IFN-cs polypeptides can be produced by any known method. DNA sequences encoding IFN-co may be synthesized using standard methods. In many embodiments, IFN-a polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e. g., E coli, or in eukaryotic host cells (e. g. , yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-co is"recombinant IFN- (»."Where the host cell is a bacterial host cell, the IFN-m is modified to comprise an N- terminal methionine.

[001157] It is to be understood that IFN-co as described herein may comprise one or more modified amino acid residues, e. g. , glycosylations, chemical modifications, and the like.

Type III interferon receptor agonists [001158] In certain of the subject methods, an interferon receptor agonist is administered. The interferon receptor agonist is in some embodiments an agonist of a Type III interferon receptor (e. g. ,"a Type III interferon receptor agonist"). Type III interferon agonists include an IL-28b polypeptide; an IL-28a polypeptide; an IL-29 polypeptide; antibody specific for a Type III interferon receptor; and any other agonist of Type III interferon receptor, including non- polypeptide agonists.

[001159] IL-28A, IL-28B, and IL-29 (referred to herein collectively as"Type III interferons"or "Type III IFNs") are described in Sheppard et al. (2003) Nature 4: 63-68. Each polypeptide binds a heterodimeric receptor consisting of IL-10 receptor (3 chain and an IL-28 receptor a.

Sheppard et al. (2003), supra. The amino acid sequences of IL-28A, IL-28B, and IL-29 are found under GenBank Accession Nos. NP_742150, NP_742151, and NP_742152, respectively.

[001160] The amino acid sequence of a Type III IFN receptor polypeptide agonist may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i. e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non- conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine) ; (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[001161] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e. g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e. g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e. g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e. g. phosphotyrosine, phosphoserine, or phosphothreonine.

[001162] Also suitable for use in a subject method are polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone of the peptide may be cyclized to enhance stability (see Friedler et al.

(2000) J. Biol. Chem. 275: 23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e. g. D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability. The polypeptides may be fused to albumin.

[001163] The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cystines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.

Type II Interferon receptor agonists [001164] Type II interferon receptor agonists include any naturally occurring or non-naturally- occurring ligand of a human Type II interferon receptor that binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[001165] A specific example of a Type II interferon receptor agonist is IFN-gamma and variants thereof. While the present invention exemplifies use of an IFN-gamma polypeptide, it will be readily apparent that any Type II interferon receptor agonist can be used in a subject method.

Interferon-Gamma [001166] The nucleic acid sequences encoding IFN-gamma polypeptides may be accessed from public databases, e. g. , Genbank, journal publications, and the like. While various mammalian IFN-gamma polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN-gamma coding sequence may be found in Genbank, accession numbers X13274 ; V00543; and Nom 000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265; and V00536. See, for example. Gray et al. (1982) Nature 295: 501 (Genbank X13274); and Rinderknecht et al.

(1984) J B. C 259: 6790.

[001167] IFN-ylb (Actimmune (g) ; human interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinantly in E. coli and is unglycosylated (Rinderknecht et al. 1984, J.

Biol. Chem. 259: 6790-6797). Recombinant IFN-gamma as discussed in U. S. Patent No.

6,497, 871 is also suitable for use herein.

[001168] The IFN-gamma to be used in the methods of the present invention may be any of natural IFN-gamma, recombinant IFN-gamma and the derivatives thereof so far as they have an IFN-y activity, particularly human IFN-gamma activity. Human IFN-gamma exhibits the antiviral and anti-proliferative properties characteristic of the interferons, as well as a number of other immunomodulatory activities, as is known in the art. Although IFN-gamma is based on the sequences as provided above, the production of the protein and proteolytic processing can result in processing variants thereof. The unprocessed sequence provided by Gray et al., supra, consists of 166 amino acids (aa). Although the recombinant IFN-gamma produced in E. coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN-gamma is cleaved after residue 23, to produce a 143 aa protein, or 144 aa if the terminal methionine is present, as required for expression in bacteria. During purification, the mature protein can additionally be cleaved at the C terminus after reside 162 (referring to the Gray et al. sequence), resulting in a protein of 139 amino acids, or 140 amino acids if the initial methionine is present, e. g. if required for bacterial expression. The N-terminal methionine is an artifact encoded by the mRNA translational "start"signal AUG that, in the particular case of E. coli expression is not processed away. In other microbial systems or eukaryotic expression systems, methionine may be removed.

[001169] For use in the subject methods, any of the native IFN-gamma peptides, modifications and variants thereof, or a combination of one or more peptides may be used. IFN-gamma peptides of interest include fragments, and can be variously truncated at the carboxyl terminus relative to the full sequence. Such fragments continue to exhibit the characteristic properties of human gamma interferon, so long as amino acids 24 to about 149 (numbering from the residues of the unprocessed polypeptide) are present. Extraneous sequences can be substituted for the amino acid sequence following amino acid 155 without loss of activity. See, for example, U. S. Patent No. 5,690, 925. Native IFN-gamma moieties include molecules variously extending from amino acid residues 24-150; 24-151,24-152 ; 24-153,24-155 ; and 24-157. Any of these variants, and other variants known in the art and having IFN-y activity, may be used in the present methods.

[001170] The sequence of the IFN-gamma polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i. e. , will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes.

Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[001171] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e. g. , acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. IFN-gamma may be modified with one or more polyethylene glycol moieties (PEGylated) as described above for IFN-alpha. In one embodiment, the invention contemplates the use of IFN-gamma variants with one or more non-naturally occurring glycosylation and/or pegylation sites that are engineered to provide glycosyl-and/or PEG-derivatized polypeptides with reduced serum clearance, such as the IFN-gamma polypeptide variants described in International Patent Publication No. WO 01/36001 and WO 02/081507. Also included are modifications of glycosylation, e. g. , those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e. g. , by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e. g., phosphotyrosine, phosphoserine, or phosphothreonine.

[001172] Included for use in a subject method are polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone of the peptide may be cyclized to enhance stability (see, for example, Friedler et al. 2000, J. Biol. Chem. 275: 23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e. g. , D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability.

[001173] The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.

[001174] The polypeptides may also be isolated and purified in accordance with conventional methods of recombinant synthesis. A lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. For the most part, the compositions which are used will comprise at least 20% by weight of the desired product, more usually at least about 75% by weight, preferably at least about 95% by weight, and for therapeutic purposes, usually at least about 99.5% by weight, in relation to contaminants related to the method of preparation of the product and its purification. Usually, the percentages will be based upon total protein.

Pirfenidone and Analogs Thereof [001175] Pirfenidone (5-methyl-1-phenyl-2- (lH)-pyridone) and specific pirfenidone analogs can be used in certain methods of the subject invention.

Pirfenidone Pirfenidone analogs Descriptions for Substituents Rl, R2, X [001176] RI : carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alkyls (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.

[001177] Rl can further include substitutions on the carbocyclic or heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2,5-dichlorocyclohexyl, guanidinyl- cyclohexenyl and the like.

[001178] R2 : alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.

[001179] X: may be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring. The substituents can be the same or different. Substituents can include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like.

[001180] The substituents may be optionally further substituted with 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halo groups. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.

[001181] Specific Examples include those shown in Table 1: Table 1 IA IIB 5-Methyl-1-(2'-pyridyl)-2-(1 H) pyridine, 6-Methyl-l-phenyl-3- H) pyridone, 6-Methyl-l-phenyl-2- (lH) pyridone, 5-Methyl-l-p-tolyl-3- (lH) pyridone, 5-Methyl-3-phenyl-1- (2'-thienyl)-2- (lH) 5-Methyl-1- (2'-naphthyl)-3- (1H) pyridone, pyridone, 5-Methyl-l- (2'-naphthyl)-2- (lH) pyridone, 5-Methyl-l-phenyl-3- (lH) pyridone, 5-Metliyl-l-p-tolyl-2- (lH) pyridone, 5-Methyl-l- (5'-quinolyl)-3- (lH) pyridone, 5-Methyl-l- (l'naphthyl)-2- (lH) pyridone, 5-Ethyl-l-phenyl-3- (lH) pyridone, 5-Ethyl-1-phenyl-2-(1H0 pyridone, 5-Methyl-1-(4'-methoxyphenyl)-3-(1H0 pyridone, 5-Methyl-1-(5'-quinolyl)-2-(lH) pyridone, 4-Methyl-l-phenyl-3-(lH) pyridone, 5-Methyl-1-(4'-quinolyl)-2-(1H) pyridone, 5-Methyl-1-(3'-pyridyl)-3-(1H0 pyridone, 5-Methyl-1-(4'-pyridyl)-2-(1H) pyridone, 5-Methyl-l- (2'-Thienyl)-3- (lH) pyridone, 3-Methyl-1-phenyl-2-(1H) pyridone, 5-Methyl-1-(2'-pyridyl)-3-(1H) pyridone, 5-Methyl-1-(4'-methoxyphenyl)-2-(1H) 5-Methyl-1-(2'-quinolyl)-3-(1H) pyridone, pyridone 1-Phenyl-2-(1H) pyridone, 1-Phenyl-3- (1H) yridine, 1, 3-Diphenyl-2-(1H) pyridone, 1-(2'-Furyl)-5-methyl-3-(1H) pyridone, 1, 3-Diphenyl-5-methyl-2- (lH) pyridone, 1- (4'-Chlorophenyl)-5-methyl-3- (lH) pyridine. 5-Methyl-1-(3'-trifluoromethylphenyl)-2- (lH)-pyridone, 3-Ethyl-1-phenyl-2-(1H) pyridone, 5-Methyl-1-(3'-pyridyl)-2-(1H) pyridone, 5-Methyl-1- (3-nitrophenyl)-2- (1 H) pyridone, 3-(4'-Chlorophenyl)-5-Methyl-1-phenyl-2- (1 pyridone, 5-Methyl-1-(2'-Thienyl)-2-(1H) pyridone, 5-Methyl-1-(2'-thiazolyl)-2-(1H) pyridone, 3, 6-Dimethyl-1-phenyl-2-(1H) pyridone, 1- (4'Chlorophenyl)-5-Methyl-2- (lH) pyridone, l- (2'-Imidazolyl)-5-Methyl-2- (lH) pyridone, 1-(4'-Nitrophenyl)-2-(1H) pyridone, 1-2'-Fu 1)-5-Methyl-2- (1 H) ridone, 1-Phenyl-3- (4'-chlorophenyl)-2- (lH) pyridine.

[001182] U. S. Pat. Nos. 3,974, 281; 3,839, 346; 4,042, 699; 4,052, 509; 5,310, 562; 5,518, 729; 5,716, 632; and 6,090, 822 describe methods for the synthesis and formulation of pirfenidone and specific pirfenidone analogs in pharmaceutical compositions suitable for use in the methods of the present invention.

SAPK inhibitors [001183] In some embodiments, SAPK inhibitors suitable for use in a subject treatment method specifically include pirfenidone and pirfenidone analogs; and also specifically include any compound of Formula I as set forth in U. S. Patent Publication No. 20030149041. In other embodiments, SAPK inhibitors suitable for use in a subject treatment method specifically exclude pirfenidone and pirfenidone analogs; and also specifically exclude any compound of Formula I as set forth in U. S. Patent Publication No. 20030149041.

[001184] Additional SAPK inhibitors suitable for use herein include agents that inhibit enzymatic activity of a SAPK by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%,/or at least about 90%, or more, when compared with the enzymatic activity of the SAPK in the absence of the SAPK inhibitor.

[001185] The signal transduction pathways that use mitogen-activated protein kinases (MAPK) have an important role in a variety of cellular responses, including growth, stress-induced gene expression, and compensation for alterations in the environment. The SAPK group of MAPKs includes the c-Jun N-terminal Kinase (JNK) and p38 kinases. The p38 group of MAPK include at least four members, designated p38 or p38a, p38p, p38y, and p388. The amino acid sequences of p38a, p38p, and p38y from various species are known. For example, the amino acid sequences of human p38a, p38p, and p38y are found under the following GenBank Accession Nos.: 1) Q16539, NP620583, and NP001306 provide amino acid sequences of human p38a polypeptides; 2) NP620478, NP002742, and Q15759 provide amino acid sequences of human p38P polypeptides; and 3) NP002960, P53778, and JC5252 provide amino acid sequences of human p38y polypeptides.

[001186] In some embodiments, a suitable SAPK inhibitor is an agent that inhibits enzymatic activity of p38a, p38ß, and p38y. In other embodiments, a suitable SAPK inhibitor is an agent that preferentially inhibits the enzymatic activity of p38a and p38ß, i. e., the agent is a stronger inhibitoroftheenzymatic activityofp38aandp38ß thanthatofp38y, e. g. , the agent's IC50 against p38a and p380 is at least about two-fold lower, or about five-fold lower, or about ten- fold lower, or more, below the agent's IC50 against p38y.

[001187] In other embodiments, a suitable SAPK inhibitor is an agent that preferentially inhibits p38y, i. e. , the agent is a stronger inhibitor of the enzymatic activity of p38y than that of p38a and p38p, e. g. , the agent's IC50 against p38y is at least about two-fold lower, or about five- fold lower, or about ten-fold lower, or more, below the agent's IC50 against p38a and p38 (3.

[001188] In some embodiments, a SAPK inhibitor is a competitive inhibitor of a SAPK, e. g. , a p38a, a p38ß, or a p38y. In some of these embodiments, a SAPK inhibitor is one that competes for adenosine triphosphate (ATP) for binding to the ATP binding site of p38a, p38 (3, or p38y.

[001189] In addition, stress-activated protein kinase (SAPK) inhibitors that are suitable for use in a subject combination therapy include any 2-alkyl imidazole as disclosed in U. S. Patent No.

6,548, 520; any of the 1,4, 5-substituted imidazole compounds disclosed in U. S. Patent No.

6,489, 325; 1,4, 5-substituted imidazole compounds disclosed in U. S. Patent No. 6,569, 871; heteroaryl aminophenyl ketone compounds disclosed in Published U. S. Patent Application No.

2003/0073832; pyridyl imidazole compounds disclosed in U. S. Patent No. 6,288, 089; and heteroaryl aminobenzophenones disclosed in U. S. Patent No. 6,432, 962. Also suitable for use are compounds disclosed in U. S. Patent No. 6,214, 854. Also suitable for use are the heterocyclic compounds discussed in WO 99/61426.

[001190] As discussed above, in some embodiments, compounds of Formula I of U. S. Patent Publication No. 20030149041 are specifically included; and in other embodiments, compounds of Formula I of U. S. Patent Publication No. 20030149041 are specifically excluded.

[001191] Formula I of U. S. Patent Publication No. 20030149041 is as follows: Formula I (20030149041) [001192] wherein: Rl is chosen from--H, Cl to C20 hydrocarbon, aminocarbonylalkyl, alkoxyalkyl, substituted arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl ; [001193] R is chosen from halogen, Cl to C20 hydrocarbon, hydroxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl; wherein [001194] Rs is chosen from--H, alkyl and substituted alkyl ; [001195] R6 is chosen from a direct bond, alkyl, aryl, substituted aryl and heteroaryl; [001196] R7 is chosen from--H, acyl, alkyl, substituted alkyl, alkoxycarbonyl, amidine, aryl, arylalkyl, heterocyclyl, heteroaryl, substituted heteroaryl, substituted aryloxy, heteroarylsulfonamido, dialkylsulfonamido, [001197]--C (O) NR8R9,--C (NH) NR8R9and-NR8R9 ; wherein [001198] R is chosen from--H and alkyl ; [001199] R9 is chosen from--H, alkyl, substituted alkyl, aryl, heteroaryl, alkylcarbonyl and arylcarbonyl; [001200] R3 is chosen from a direct bond, [001201] wherein the left hand bond is the point of attachment to the ring and the right band bond is the point of attachment to R4 ; [001202] R4 is chosen from--H, halogen, alkyl, heterocyclyl, alkylamino, aminocarbonyl, [001203] -C(S)NHR12, --CHR13R14, --C(O)NHR15, --C(O)(CH2)0-2R16, --S(O2)R17, --OR18, [001204] wherein Rio is chosen from--H,--OH, alkyl, cycloalkyl and substituted cycloalkyl ; R is chosen from--H,--OH,--COOH, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, aminocarbonyl, aminocarbonylalkyl, [001205] R12 is chosen from alkyl and aryl; R13 is chosen from--H and aryl; R14 is chosen from aryl, substituted aryl, heteroaryl, substituted alkyl, aryl substituted alkyl and alkoxy substituted alkyl ; R15 is chosen from alkyl, aryl, substituted aryl and substituted alkyl ; Rl6 is chosen from aryl, substituted aryl, heteroaryl, carboxyl, alkoxy, substituted alkyl, cycloalkyl, substituted cycloalkyl, aminocarbonyl, substituted aminocarbonyl, heterocyclyl and [001206] Rl7 is chosen from alkyl and dialkylamino; Rl8 is chosen from Cl to C2o hydrocarbon, substituted Cl to C20 hydrocarbon and heteroaryl; Y is chosen from--H and lower alkyl, or Y and Rl taken together with the attached N, may be chosen from heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; wherein at least two of X, Xl and X2 are- N=, and the other is chosen from--C (H) = and--N=.

[001207] Of particular interest in some embodiments is use of any of the following SAPK inhibitor compounds, or pharmaceutically acceptable salts, or derivatives, or esters, or analogs, thereof : [001208] which compound has the IUPAC designation (4-benzyl-piperidin-1-yl)-(lH-indol-5- yl)-methanone. Also suitable for use are any of the following compounds: (4-benzyl-piperidin- 1-yl)-(6-chloro-lH-indol-5-yl)-methanone ; (4-chloro-lH-indol-5-yl)- [4- (4-fluoro-benzyl)- piperidin-1-yl]-methanone ; (4-benzyl-piperidin-1-yl)- (4-methoxy-lH-inol-5-yl)-methanone ; (4-Benzyl-piperidin-1-yl)- {1- [3-(cyclohexylmethyl-amino)-2-hydroxy-propyl]-1 H-indol-5-yl}- methanone; (4-Benzyl-piperidin-1-yl)-{1-[2-hydroxy-3-(4-methyl-piperazi n-1-yl)-propyl]-lH- indol-5-yl}-methanone ; [1- (3-Benzylamino-2-hydroxy-propyl)-lH-indol-5-yl]- (4-benzyl- piperidin-1-yl)-methanone ; (4-Benzyl-piperidin-1-yl)-11- [2-hydroxy-3- (4-methoxy- benzylamino)-propyl]-lH-indol-5-yl}-methanone ; (4-Benzyl-piperidin-1-yl)- [1- (2-hydroxy-3- propylamino-propyl)-lH-indol-5-yl]-methanone ; (4-Benzyl-piperidin-1-yl)- [1- (pyridine-4- carbonyl)-1 H-indol-5-yl]-methanone ; 1- [5- (4-Benzyl-piperidine-1-carbonyl)-indol-1-yl]- ethanone; 2- [5- (4-Benzyl-piperidine-1-carbonyl)-indol-1-yl]-N- (4-methoxy-benzyl)- acetamide; 5- (4-Benzyl-piperidine-1-carbonyl)-1H-indole-3-carboxylic acid (2-methoxy- ethyl)-amide ; 5-(4-Benzyl-piperidine-1-carbonyl)-1H-indole-3-carboxylic acid (2- methylamino-ethyl) -amide; 5- (4-Benzyl-piperidine-1-carbonyl)-1H-indole-3-carboxylic acid (2-amino-ethyl) -amide; [3-(4-Benzyl-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-benzyl - piperidin-1-yl)-methanone ; [3- (4-Benzyl-piperidine-1-carbonyl)-1 H-indol-6-yl]- (4-benzyl- piperidin-1-yl)-methanone ; 5- (4-Benzyl-piperidine-1-carbonyl)-1H-indole-3-carboxylic acid 4- fluoro-benzylamide; 5- (4-Benzyl-piperidine-1-carbonyl)-1H-indole-3-carboxylicacid [2- (3, 5- dimethoxy-phenyl) -ethyl] -amide ; (4-Benzyl-piperidin-1-yl)- H-indol-5-yl)- methanone ; 1- [5- (4-Benzyl-piperidine-1-carbonyl)-1H-indol-3-yl]-2, 2, 2-trifluoro-ethanone ; 5- (4-Benzyl-piperidine-1-carbonyl)-6-methoxy-1H-indole-3-carbo xylic acid (2-dimethylamino- ethyl) -amide; 5-(4-Benzyl-piperidine-1-carbonyl)-1H-indole-3-carboxylic acid; 5-(4-Benzyl- piperidine-1-carbonyl)-1 H-indole-3-carboxylic acid (2-dimethylamino-ethyl)-amide ; (1H- Benzoimidazol-5-yl)- (4-benzyl-piperidin-1-yl)-methanone ; (lH-Benzoimidazol-5-yl)- [4- (4- fluoro-benzyl) -piperidin-1-yl] -methanone ; (4-Benzyl-piperidin-1-yl)- (3-morpholin-4-ylmethyl- 1 H-indol-5-yl)-methanone ; 1- [6- (4-Benzyl-piperidine-1-carbonyl)-1 H-indol-3-yl]-2, 2, 2- trifluoro-ethanone; (4-Benzyl-piperidin-1-yl)- [l- (pyridine-4-carbonyl)-lH-indol-6-yl]- methanone ; (3-Benzyl-8-aza-bicyclo [3.2. 1] oct-8-yl)- (6-methoxy-1H-indol-5-yl)-methanone ; (3H-Benzoimidazol-5-yl)-(3-benzyl-8-aza-bicyclo [3.2. 1] oct-8-yl) -methanone ; [3- (4-Fluoro- benzyl)-pyrrolidin-1-yl]- (lH-indol-6-yl)-methanone ; (1H-Benzoimidazol-5-yl)- [4- (2, 6- difluoro-benzyl)-piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)- [4- (4-methylsulfanyl- benzyl)-piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)- [4- (2, 3-difluoro-benzyl) - piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)- [4- (3, 5-difluoro-benzyl)-piperazin-1-yl]- methanone; (lH-Benzoimidazol-5-yl)- [4- (3-chloro-benzyl)-piperazin-1-yl]-methanone ; 4- [4- (lH-Benzoimidazole-5-carbonyl)-piperazin-1-ylmethyl]-benzoic acid methyl ester ; (1H- Benzoimidazol-5-yl)- [4- (4-methoxy-benzyl)-piperazin-1-yl]-methanone ; (IH-Benzoimidazol- 5-yl)- [4- (4-trifluoromethoxy-benzyl)-piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)- [4- (4-methyl-benzyl)-piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)- [4- (2, 4-dichloro- benzoyl)-piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)- [4- (3, 4-dichloro-benzoyl) - piperazin-1-yl]-methanone ; trans-1-[4-(1H-Benzoimidazole-5-carbonyl)-piperazin-1-yl]-3- (3- trifluoromethyl-phenyl) -propenone; (lH-Benzoimidazol-5-yl)- [4- (4-chloro-benzoyl)- piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)- (4-benzoyl-piperazin-1-yl)-methanone ; (1H-Benzoimidazol-5-yl)-[4-(2-trifluoromethyl-benzoyl)-piper azin-1-yl]-methanone ; (1H- Benzoimidazol-5-yl)- [4- (4-methoxy-benzoyl)-piperazin-1-yl]-methanone ; (lH-Benzoimidazol- 5-yl)- [4- (3, 4-dichloro-phenyl)-piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)- {4- [ (4- chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-methanone ; trans- (lH-Benzoimidazol-5-yl)- [4- (3-phenyl-allyl)-piperazin-1-yl]-methanone ; (lH-Benzoimidazol-5-yl)-{4-[bis-(4-fluoro- phenyl)-methyl]-piperazin-1-yl}-methanone ; (lH-Benzoimidazol-5-yl)- [4- (4-chloro-benzyl)- piperazin-1-yl] -methanone; (1 H-Benzoimidazol-5-yl)- [4-(2-chloro-benzyl)-piperazin-1-yl]- methanone ; (lH-Benzoimidazol-5-yl)- [4- (3, 4, 5-trimethoxy-benzyl)-piperazin-1-yl]- methanone; (1H-Benzoimidazol-5-yl)-[4-(4-diethylamino-benzyl)-piperazin -1-yl]-methanone ; (1H-Benzoimidazol-5-yl)-(4-biphenyl-4-ylmethyl-piperazin-1-y l)-methanone ; (1H- Benzoimidazol-5-yl)- [4- (4-phenoxy-benzyl)-piperazin-1-yl]-methanone ; (4-Benzyl-piperidin- 1-yl)-(6-methoxy-lH-benzoimidazol-5-yl)-methanone ; (4-Benzyl-piperidin-1-yl)-(l-isopropyl- lH-benzoimidazol-5-yl)-methanone ; (4-Benzyl-piperidin-1-yl)-(3-isopropyl-3H- benzoimidazol-5-yl) -methanone; (4-Benzyl-piperidin-1-yl)- H-indol-5-yl)- methanone; [4-(4-Chloro-benzyl)-piperazin-1-yl]-(1-isopropyl-1H-indol-5 -yl)-methanone ; (lH-Benzotriazol-5-yl)- (4-benzyl-piperidin-1-yl)-methanone ; (4-Benzyl-piperidin-1-yl)-(l- isopropyl-1H-benzotriazol-5-yl)-methanone ; [4- (4-Chloro-benzyl)-piperidin-1-yl]- (lH-indol- 5-yl) -methanone; [4- (3-Chloro-benzyl)-piperidin-1-yl]- (lH-indol-5-yl)-methanone ; [4- (2- Chloro-benzyl)-piperidin-1-yl]- (1H-indol-5-yl)-methanone ; (4-Benzyl-2-methyl-piperidin-1- yl)-(lH-indol-5-yl)-methanone ; (4-Benzyl-piperidin-1-yl)-(4-chloro-1H-indol-5-yl)- methanone; (4-Benzyl-piperidin-1-yl)-[7-chloro-1-(pyridine-3-carbonyl)- 1H-indol-6-yl]- methanone; (4-Benzyl-piperidin-1-yl)- (5-chloro-1H-indol-6-yl)-methanone ; (4-Benzyl- piperidin-1-yl)- (7-chloro-1H-indol-6-yl)-methanone ; 6- (4-Benzyl-piperidine-1-carbonyl)-7- chloro-1- (pyridine-3-carbonyl)-1H-indole-3-carbonxylic acid (2-dimethylamino-ethyl) -amide ; (4-Benzyl-piperidin-1-yl)- (1-pyridin-4-ylmethyl-1H-indol-5-yl)-methanone ; (4-Benzyl- piperidin-1-yl)- [6-methoxy-1- (pyridine-3-carbonyl)-1H-indol-5-yl]-methanone ; [5- (4-Benzyl- piperidine-l-carbonyl)-indol-l-yl]-acetic acid methyl ester; 1- [5- (4-Benzyl-piperidine-1- carbonyl)-indol-l-yl]-3-isopropylamino-propan-1-one ; 1- [5- (4-Benzyl-piperidine-l-carbonyl)- indol-1-yl]-3-piperazin-1-yl-propan-1-one ; 3-Benzylamino-1- [5- (4-benzyl-piperidine-1- carbonyl)-indol-1-yl]-propan-1-one ; 1- [5- (4-Benzyl-piperidine-l-carbonyl)-indol-1-yl]-3- morpholin-4-yl-propan-1-one; 2- [5- (4-Benzyl-piperidine-1-carbonyl)-indol-1-yl]-N-propyl- acetamide; (4-Benzyl-piperidin-l-yl)-[l-(2-diethylamino-ethyl)-6-methox y-lH-indol-5-yl]- methanone; (4-Benzyl-piperidin-1-yl)- [1- (3-diethylamino-propyl)-1H-indol-5-yl]-methanone ; (4-Benzyl-piperidin-1-yl)- [l- (2-diethylamino-ethyl)-lH-indol-5-yl]-methanone ; (4-Benzyl- piperidin-l-yl)-[6-chloro-1-(3-diethylamino-propyl)-1 H-indol-5-yl]-methanone ; [1-(2- Diethylamino-ethyl)-lH-indol-5-yl]- [4- (4-fluoro-benzyl)-piperidin-1-yl]-methanone ; (4- Benzyl-piperidin-1-yl)- [l- (3-diethylamino-propyl)-6-methoxy-lH-indol-5-yl]-methanone ; 5- (4-Benzyl-piperidine-l-carbonyl)-lH-indole-3-carboxylic acid (2-amino-ethyl) -methyl-amide; 5-(4-Benzyl-piperidine-1-carbonyl)-1H-indole-3-carboxylic acid [2-(3,4-dimethoxy-phenyl)- ethyl] -amide; (4-Benzyl-piperidin-1-yl)- H-indol-5-yl)-methanone ; [4- (4-Fluoro-benzyl)-piperidin-, l-yl]- (6-methoxy-lH-indol-5-yl)-methanone ; (4-Benzyl-piperidin- 1-yl)- (1-pyridin-4-yl-1H-indol-5-yl)-methanone ; and 4 (4-Benzyl-piperidin-1-yl)- (4-chloro-2- methyl-lH-indol-5-yl)-methanone ; or pharmaceutically acceptable salts, or derivatives, or esters, or analogs, of any of the foregoing compounds.

[001209] Of particular interest in some embodiments is use of any of the following SAPK inhibitor compounds, or pharmaceutically acceptable salts, or derivatives, or esters, or analogs, thereof : [001210] which compound has the IUPAC designation' [2- (2-Chloro-phenyl)-quinazolin-4-yl]- pyridin-4-yl-amine. Also suitable for use are any of the following compounds: [2- (2, 6- Dichloro-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine ; Pyridin-4-yl- (2-o-tolyl-quinazolin-4- yl) -amine; [2- (2-Bromo-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine ; [2- (2-Fluoro-phenyl)- quinazolin-4-yl] -pyridin-4-yl-amine; [2- (2, 6-Difluoro-phenyl) -quinazolin-4-yl]-pyridin-4-yl- amine; (2-Phenyl-quinazolin-4-yl) -pyridin-4-yl-amine; [2- (4-Fluoro-phenyl)-quinazolin-4-yl]- pyridin-4-yl-amine ; [2- (4-Methoxy-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine ; [2- (3-Fluoro- phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine ; Isopropyl- (2-phenyl-quinazolin-4-yl)-pyridin-4- yl-amine ; (4-Methoxy-benzyl)- (2-phenyl-quinazolin-4-yl)-pyridin-4-yl-amine ; (2-Phenyl- quinazolin-4-yl)-pyridin-4-ylmethyl-amine ; [2- (4-Chloro-phenyl)-quinazolin-4-yl]-pyridin-4- ylmethyl-amine; (2-Phenyl-quinazolin-4-yl) -pyridin-3-yl-amine; (2-Phenyl-quinazolin-4-yl) - pyridin-2-ylmethyl-amine ; (2-Phenyl-quinazolin-4-yl)-pyridin-3-ylmethyl-amine ; (2-Phenyl- quinazolin-4-yl)- (2-pyridin-2-yl-ethyl)-amine ; (2-Phenyl-quinazolin-4-yl)-pyrimidin-4-yl- amine ; (2-Phenyl-quinazolin-4-yl)-pyrimidin-2-yl-amine ; Phenyl- (2-phenyl-quinazolin-4-yl)- amine ; Benzyl- [2- (3-chloro-phenyl)-quinazolin-4-yl]-amine ; 3- (2-Phenyl-quinazolin-4- <BR> <BR> <BR> <BR> ylamino) -phenol; 2-(2-Phenyl-quinazolin-4-ylamino)-phenol ; 4- (2-Phenyl-quinazolin-4-<BR> <BR> <BR> <BR> <BR> ylamino) -phenol; (lH-Indol-4-yl)- (2-phenyl-quinazolin-4-yl)-amine ; (IH-Indol-5-yl)- (2- phenyl-quinazolin-4-yl)-amine ; (4-Methoxy-phenyl)- (2-phenyl-quinazolin-4-yl)-amine ; (3- Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-amine ; (2-Methoxy-phenyl)- (2-phenyl- quinazolin-4-yl)-amine ; 2- [4- (2-Phenyl-quinazolin-4-ylamino)-phenyl]-ethanol ; 3- (2-Phenyl- quinazolin-4-ylamino)-benzonitrile ; (2, 5-Difluoro-benzyl)- (2-phenyl-quinazolin-4-yl)-amine ; [4- (2-Butyl)-phenyl]- (2-phenyl-quinazolin-4-yl)-amine ; N, N-Dimethyl-N'- (2-phenyl- quinazolin-4-yl)-benzene-1, 4-diamine ; [2-(2-Chloro-phenyl)-6, 7-dimethoxy-quinazolin-4-yl]- pyridin-4-yl-amine ; [2- (2-Fluoro-phenyl)-6-nitro-quinazolin-4-yl]-pyridin-4-yl-amin e ; 2- (2- Fluoro-phenyl)-N4-pyridin-4-yl-quinazoline-4, 6-diamine ; 2- (2-Fluoro-phenyl)-N4-pyridin-4- yl-quinazoline-4, 7-diamine ; 2- (2-Fluoro-phenyl)-N6- (3-methoxy-benzyl)-N4-pyridin-4-yl- quinazoline-4, 6-diamine; 2- (2-Fluoro-phenyl)-N6- (4-methoxy-benzyl)-N4-pyridin-4-yl- quinazoline-4, 6-diamine ; N6-Isobutyl-2- (2-fluoro-phenyl)-N4-pyridin-4-yl-quinazoline-4, 6- diamine ; 2- (2-Fluoro-phenyl)-N6- (4-methylsulfanyl-benzyl)-N4-pyridin-4-yl-quinazoline-4, 6- diamine ; 4- (4-Pyridylamino)-2- (4-chlorophenyl) quinazoline ; 2-Phenyl-4- (2-pyridylamino)- quinazoline; and [2- (2-Fluoro-phenyl)-pyrido [2,3-d] pyrimidin-4-yl]-pyridin-4-yl-amine ; or pharmaceutically acceptable salts, or derivatives, or esters, or analogs, of any of the foregoing compounds.

[001211] A further suitable SAPK inhibitor is BIRB796 (1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3- yl)-3- [4- (2-morpholin-4-yl-e- thoxy)-naphthalen-1-yl]-urea) ; see U. S. Patent no. 6, 319, 921.

[001212] BIRB796 has the following structure: [001213] Also suitable for use are pharmaceutically active derivatives, analogs, esters, prodrugs, and salts of BIRB796.

[001214] Another suitable SAPK inhibitor is 2 (1H)-quinazolinone, as shown below: [001215] Also suitable for use are pharmaceutically active derivatives, analogs, esters, prodrugs, and salts of 2 (1H)-quinazolinone.

[001216] Additionally suitable for use is VX-745 (Vertex Pharmaceuticals and Kissei Pharmaceutical Co. ) VX-745 has been reported to inhibit several isotypes of p38, including p38-alpha, p38-beta and p38-gamma.

[001217] Methods of measuring SAPK activity are known in the art. One non-limiting example of an assay to measure enzymatic activity of a SAPK is as follows. In a final reaction volume of 25 al, SAPK2a (p38a ; 5-10 mU) is incubated with 25 mM Tris pH 7.5, 0.02 mM EGTA, 0. 33 mg/ml myelin basic protein, 10 mM magnesium acetate and [y-33P-ATP] (specific activity approximately 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by addition of 5 ul of a 3% phosphoric acid solution. Ten gel of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once more in methanol prior to drying and scintillation counting.

[001218] Another example of an assay for testing the effect of an agent on p38 kinase activity is as follows. A compound to be tested is solubilized in dimethylsulfoxide and diluted into water.

The p38 kinase is diluted to 10 llg/ml into a buffer containing 20 mM mOPS, pH 7.0, 25 mM beta-glycerol phosphate, 2 mg/ml gelatin, 0.5 mM EGTA, and 4 mM DTT. The reaction is carried out by mixing 20 u. l test compound with 10 u. l of a substrate cocktail containing 500 llg/ml peptide substrate and 0.2 mM ATP (+ 200 ßCi/ml y-32P-ATP) in a 4x assay buffer. The reaction is initiated by the addition of 10 u. l p38 kinase. Final assay conditions are 25 mM MOPS, p 7.0, 26.25 mM beta-glycerol phosphate, 80 mM KCI, 22 mM MgCl2, 3 mM MgS04, 1 mg/ml gelatin, 0.625 mM EGTA, 1 mM DTT, 125 Zg/ml peptide substrate, 50 uM APT, and 2.5 u. g/ml enzyme. The reaction is stopped by the addition of 10 pl 0. 25 M phosphoric acid.

Activity is determined by measuring incorporation of radioactivity into the peptide substrate.

TNF Antagonists [001219] Suitable TNF-a antagonists for use herein include agents that decrease the level of TNF-a synthesis, agents that block or inhibit the binding of TNF-a to a TNF-a receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction. Unless otherwise expressly stated, every reference to a"TNF-a antagonist"or"TNF antagonist" herein will be understood to mean a TNF-a antagonist other than pirfenidone or a pirfenidone analog.

[001220] As used herein, the terms"TNF receptor polypeptide"and"TNFR polypeptide"refer to polypeptides derived from TNFR (from any species) which are capable of binding TNF. Two distinct cell-surface TNFRs have described: Type II TNFR (or p75 TNFR or TNFRII) and Type I TNFR (or p55 TNFR or TNFRI). The mature full-length human p75 TNFR is a glycoprotein having a molecular weight of about 75-80 kilodaltons (kD). The mature full- length human p55 TNFR is a glycoprotein having a molecular weight of about 55-60 kD.

Exemplary TNFR polypeptides are derived from TNFR Type I and/or TNFR type II. Soluble TNFR includes p75 TNFR polypeptide ; fusions of p75 TNFR with heterologous fusion partners, e. g. , the Fc portion of an immunoglobulin.

[001221] TNFR polypeptide may be an intact TNFR or a suitable fragment of TNFR. U. S. Pat.

No. 5,605, 690 provides examples of TNFR polypeptides, including soluble TNFR polypeptides, appropriate for use in the present invention. In many embodiments, the TNFR polypeptide comprises an extracellular domain of TNFR. In some embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR linked to a constant domain of an immunoglobulin molecule. In other embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 TNFR linked to a constant domain of an IgGl molecule. In some embodiments, when administration to humans is contemplated, an Ig used for fusion proteins is human, e. g. , human IgGl.

[001222] Monovalent and multivalent forms of TNFR polypeptides may be used in the present invention. Multivalent forms of TNFR polypeptides possess more than one TNF binding site.

In some embodiments, the TNFR is a bivalent, or dimeric, form of TNFR. For-example, as described in U. S. Pat. No. 5,605, 690 and in Mohler et al. , 1993, J. Immunol. , 151: 1548-1561, a chimeric antibody polypeptide with TNFR extracellular domains substituted for the variable domains of either or both of the immunoglobulin heavy or light chains would provide a TNFR polypeptide for the present invention. Generally, when such a chimeric TNFR: antibody polypeptide is produced by cells, it forms a bivalent molecule through disulfide linkages between the immunoglobulin domains. Such a chimeric TNFR: antibody polypeptide is referred to as TNFR: Fc.

[001223] In one embodiment, a subject method involves administration of an effective amount of the soluble TNFR ENBRELS. ENBRELS is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNFR linked to the Fc portion of human IgGl. The Fc component of ENBREL) contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgGl. ENBRELO is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al.

(1990) Science 248: 1019-1023; Mohler et al. (1993) J Immunol. 151: 1548-1561 ; U. S. Pat. No.

5,395, 760; and U. S. Pat. No. 5,605, 690.

[001224] Also suitable for use are monoclonal antibodies that bind TNF-a. Monoclonal antibodies include"humanized"mouse monoclonal antibodies; chimeric antibodies; monoclonal antibodies that are at least about 80%, at least about 90%, at least about 95%, or 100% human in amino acid sequence; and the like. See, e. g. , WO 90/10077; WO 90/04036; and WO 92/02190. Suitable monoclonal antibodies include antibody fragments, such as Fv, F (ab') 2 and Fab; synthetic antibodies; artificial antibodies; phage display antibodies; and the like.

[001225] Examples of suitable monoclonal antibodies include Infliximab (REMICADE&commat;, Centocor); and Adalimumab (HUMIRATM, Abbott). REMICADE is a chimeric monoclonal anti-TNF-a antibody that includes about 25% mouse amino acid sequence and about 75% human amino acid sequence. REMICADE (E) comprises a variable region of a mouse monoclonal anti-TNF-a antibody fused to the constant region of a human IgGl. Elliott et al.

(1993) Arthritis Rheum. 36: 1681-1690; Elliott et al. (1994) Lancet 344: 1105-1110; Baert et al.

(1999) Gastroenterology 116: 22-28. HUMIRATM is a human, full-length IgGl monoclonal antibody that was identified using phage display technology. Piascik (2003) J. Am. Pharm.

Assoc. 43: 327-328.

[001226] Also included in the term"TNF antagonist, "and therefore suitable for use in a subject method, are stress-activated protein kinase (SAPK) inhibitors. SAPK inhibitors are known in the art, and include, but are not limited to 2-alkyl imidazoles disclosed in U. S. Patent No.

6,548, 520; 1,4, 5-substituted imidazole compounds disclosed in U. S. Patent No. 6,489, 325; 1,4, 5-substituted imidazole compounds disclosed in U. S. Patent No. 6,569, 871; heteroaryl aminophenyl ketone compounds disclosed in Published U. S. Patent Application No.

2003/0073832 ; pyridyl imidazole compounds disclosed in U. S. Patent No. 6,288, 089; and heteroaryl aminobenzophenones disclosed in U. S. Patent No. 6,432, 962. Also of interest are compounds disclosed in U. S. Patent Application Publication No. 2003/0149041; and U. S.

Patent No. 6,214, 854. Also suitable for use are the quinazoline compounds discussed in U. S.

Patent No. 6,184, 226. Also suitable for use are the heterocyclic compounds discussed in WO 99/61426. A stress-activated protein kinase is a member of a family of mitogen-activated protein kinases which are activated in response to stress stimuli. SAPK include, but are not limited to, p38 (Lee et al. (1994) Nature 372: 739) and c-jun N-terminal kinase (JNK).

[001227] Methods to assess TNF antagonist activity are known in the art and exemplified herein.

For example, TNF antagonist activity may be assessed with a cell-based competitive binding assay. In such an assay, radiolabeled TNF is mixed with serially diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions of the suspension are centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions determined. TNF antagonist activity is assessed by inhibition of TNF binding to the cells in the presence of the TNF antagonist.

[001228] As another example, TNF antagonists may be analyzed for the ability to neutralize TNF activity in vitro in a bioassay using cells susceptible to the cytotoxic activity of TNF as target cells. In such an assay, target cells, cultured with TNF, are treated with varying amounts of TNF antagonist and subsequently are examined for cytolysis. TNF antagonist activity is assessed by a decrease in TNF-induced target cell cytolysis in the presence of the TNF antagonist.

Endothelin Receptor Antagonists [001229] In some embodiments, a subject method involves administering an endothelin receptor antagonist. Endothelin receptor antagonists suitable for use in the present invention include agents that block or inhibit the binding of endothelin to an endothelin receptor, and agents that block or inhibit endothelin receptor-mediated signal transduction. In some embodiments, an endothelin receptor antagonist is selective for endothelin A (ETA) receptors. In some embodiments, an endothelin receptor antagonist is selective for endothelin B (ETB) receptors.

In other embodiments, an endothelin receptor antagonist is an antagonist of both ETA and ETB receptors.

[001230] Specific examples of endothelin antagonists useful in the present invention include, but are not limited to, atrasentan (ABT-627; Abbott Laboratories), Veletri (tezosentan; Actelion Pharmaceuticals, Ltd. ), sitaxsentan (ICOS-Texas Biotechnology), enrasentan (GlaxoSmithKline), darusentan (LU135252; Myogen) BMS-207940 (Bristol-Myers Squibb), BMS-193884 (Bristol-Myers Squibb), BMS-182874 (Bristol-Myers Squibb), J-104132 (Banyu Pharmaceutical), VML 588/Ro 61-1790 (Vanguard Medica), T-0115 (Tanabe Seiyaku), TAK- 044 (Takeda), BQ-788 (Banyu Pharmaceutical), BQ123, YM-598 (Yamanouchi Pharma), PD 145065 (Parke-Davis), A-127722 (Abbott Laboratories), A-192621 (Abbott Laboratories), A- 182086 (Abbott Laboratories), TBC3711 (ICOS-Texas Biotechnology), BSF208075 (Myogen), S-0139 (Shionogi), TBC2576 (Texas Biotechnology), TBC3214 (Texas Biotechnology), PD156707 (Parke-Davis), PD180988 (Parke-Davis), ABT-546 (Abbott Laboratories), ABT-627 (Abbott Laboratories), SB247083 (GlaxoSmithKline), SB 209670 (GlaxoSmithKline) ; and an endothelin receptor antagonists discussed in the art, e. g. , Davenport and Battistini (2002) Clinical Science 103: 15-35, Wu-Wong et al. (2002) Clinical Science 103: 1075-1115, and Luescher and Barton (2000) Circulation 102: 2434-2440.

[001231] A suitable endothelin receptor antagonist is TRACLEERTM (bosentan; manufactured by Actelion Pharmaceuticals, Ltd. ). TRACLEERTM is an orally active dual endothelin receptor antagonist, and blocks the binding of endothelin to both of its receptors endothelin receptor A and endothelin receptor B.

[001232] TRACLEERTM belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N- [6- (2-hydroxy-ethoxy)-5- (2- methoxy-phenoxy)-[2, 2']-bipyrimidin-4-yl]-benzenesulfonamide monohydrate and has the following structural formula: [001233] TRACLEERTM treatment is in some embodiments administered at a dose of 62.5 mg bid orally for 4 weeks, followed by a maintenance dose of 125 mg bid orally.

TGF-ß Antagonists [001234] In some embodiments, a subject method involves administering a TGF-ß antagonist.

TGF-ß antagonists suitable for use in a subject treatment method include agents that decrease the level of TGF-ß synthesis, agents that block or inhibit the binding of TGF-ß to a TGF-ß receptor, and agents that block or inhibit TGF-ß receptor-mediated signal transduction. As used herein, the term"TGF-p"includes any TGF-ß subtype, including TGF-ß1, TGF-ß2, and TGF-ß3. Suitable TGF-ß antagonists include, but are not limited to, antibodies specific for TGF-ß (including antibodies specific for a particular TGF-ß subtype; and antibodies cross- reactive with two or more TGF-ß subtypes); antibodies to TGF-ß receptor; soluble TGF-ß receptor; decorin; and agents that inhibit TGF-ß signaling.

[001235] Suitable TGF-ß antagonists include antibodies specific for TGF-ß. Antibodies specific for TGF-ß are known in the art. See, e. g. , U. S. Patent Nos. 5,783, 185,5, 772,998, 5,674, 843, 5,571, 714,5, 462,925, and 5,426, 098; WO 97/13844; and U. S. Patent Publication Nos 20030064069 and 20030091566. Non-limiting examples of suitable anti-TGF-ß antibodies include CAT-152 (lerdelibumab; TrabioTM ; Cambridge Antibody Technology), a human anti- TGF-ß2 monoclonal antibody; CAT-192 (metelimumab; Cambridge Antibody Technology), a human anti-TGF-ßl monoclonal antibody; and GC-1008 (Genzyme Corp. ), a pan-specific human monoclonal antibody to TGF-ß1, TGF-ß2, and TGF-ß3.

[001236] Suitable TGF-ß antagonists include soluble TGF-ß receptors. Soluble TGF-ß receptors typically lack most or all of the transmembrane portion of a naturally-occurring TGF-ß receptor, such that the protein is not membrane bound, yet retains TGF-ß binding. Soluble TGF-ß receptors include soluble fusion proteins comprising a portion of a TGF-ß receptor fused in-frame to a heterologous (non-TGF-ß receptor) protein (a"fusion partner"). Non- limiting examples of fusion partners are immunoglobulin Fc, poly-histidine, and the like.

Soluble TGF-ß receptors have been described in the art. See, e. g. , Wang et al. (1999) Thorax 54: 805-812 ; George et al. (1999) Proc. Natl. Acad. Sci. USA 96: 12719-12724; Muraoka et al.

(2002) R Clin. Invest. 109: 1551-1559; and Yata et al. (2002) Hepatology 35: 1022-1030.

[001237] TGF-ß antagonists include Gleevec. Gleevec (also known as STI-571, or CGP57148B) has the chemical name 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino-phenyl] benzamid methanesulfonate is commonly known as imatinib mesylate and sold under the trademark GleevecTM. GleevecTM is a 2- phenylaminopyrimidine that targets the ATP-binding site of the kinase domain of Bcr-Abl tyrosine kinase (see, e. g. Druker et al. (1996) Nature Med. 2, 561 ; and Buchdunger et al.

(1993) Proc. Natl. Acad. Sci. USA 92: 2558-2562).

[001238] In certain embodiments, the agents are pyrimidine derivatives as described in U. S.

Patent No. 5,521, 184, the disclosure of which is herein incorporated by reference. In these embodiments, of interest are N-phenyl-2-pyrimidine-amine derivatives of formula (I) : [001239] wherein [001240] Rl, is 4-pyrazinyl, l-methyl-lH-pyrrolyl, amino-or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, 1H-indolyl or 1H- imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl- substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R2, and R3 are each independently of the other hydrogen or lower alkyl, one or two of the radicals R4', R5', R6', R7'and R8'are each nitro, fluoro-substituted lower alkoxy or a radical of formula (II): N (R9')-C(=X)-(Y)k-R10 [001241] wherein [001242] Rg, is hydrogen or lower alkyl, [001243] X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or 0-lower alkyl- hydroximino, [001244] Y is oxygen or the group NH, [001245] k is 0 or 1 and [001246] Rlo is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic- aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical, [001247] and the remaining radicals R4*, Rs, Rs, R7, and R8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy, [001248] and salts of such compounds having at least one salt-forming group.

[001249] In these embodiments: [001250] 1-Methyl-lH-pyrrolyl is preferably l-methyl-lH-pyrrol-2-yl or 1-methyl-lH-pyrrol-3- yl.

[001251] Amino-or amino-lower alkyl-substituted phenyl Ri wherein the amino group in each case is free, alkylated or acylated, is phenyl substituted in any desired position (ortho, meta or para) wherein an alkylated amino group is preferably mono-or di-lower alkylamino, for example dimethylamino, and the lower alkyl moiety of amino-lower alkyl is preferably linear C1-C3 alkyl, such as especially methyl or ethyl.

1 H-Indolyl bonded at a carbon atom of the five-membered ring is lH-indol-2-yl or lH-indol-3- yl.

[001252] Unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom is lower alkyl-substituted or preferably unsubstituted 2-, or preferably 3-or 4-pyridyl, for example 3- pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl or 4-pyridyl. Pyridyl substituted at the nitrogen atom by oxygen is a radical derived from pyridine N-oxide, i. e. , N-oxido-pyridyl, e. g.

N-oxido-4-pyridyl.

[001253] Fluoro-substituted lower alkoxy is lower alkoxy carrying at least one, but preferably several, fluoro substituents, especially trifluoromethoxy or preferably 1,1, 2,2-tetrafluoro- ethoxy.

[001254] When X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or 0-lower alkyl- hydroximino, the group C=X is, in the above order, a radical C=O, C=S, C=N-H, C=N-lower alkyl, C=N-OH or N-lower alkyl, respectively. X is preferably oxo.

[001255] k is preferably 0, i. e. , the group Y is not present.

[001256] Y, if present, is preferably the group NH.

[001257] The term"lower"within the scope of this text denotes radicals having up to and including 7, preferably up to and including 4 carbon atoms.

[001258] Lower alkyl Rl', R2', R3'and R9'is preferably methyl or ethyl.

[001259] An aliphatic radical Rio having at least 5 carbon atoms preferably has not more than 22 carbon atoms, generally not more than 10 carbon atoms, and is such a substituted or preferably unsubstituted aliphatic hydrocarbon radical, that is to say such a substituted or preferably unsubstituted alkynyl, alkenyl or preferably alkyl radical, such as C5-C7 alkyl, for example n- pentyl. An aromatic radical Rio has up to 20 carbon atoms and is unsubstituted or substituted, for example in each case unsubstituted or substituted naphthyl, such as especially 2-naphthyl, or preferably phenyl, the substituents preferably being selected from cyano, unsubstituted or hydroxy-, amino-or 4-methyl-piperazinyl-substituted lower alkyl, such as especially methyl, trifluoromethyl, free, etherified or esterified hydroxy, free, alkylated or acylated amino and free or esterified carboxy. In an aromatic-aliphatic radical Rio the aromatic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially Cl-C2 alkyl, which is substituted or preferably unsubstituted, for example benzyl. A cycloaliphatic radical Rio has especially up to 30, more especially up to 20, and most especially up to 10 carbon atoms, is mono-or poly-cyclic and is substituted or preferably unsubstituted, for example such a cycloalkyl radical, especially such a 5-or 6-membered cycloalkyl radical, such as preferably cyclohexyl. In a cycloaliphatic-aliphatic radical Rio the cycloaliphatic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially C1-C2 alkyl, which is substituted or preferably unsubstituted. A heterocyclic radical Rio contains especially up to 20 carbon atoms and is preferably a saturated or unsaturated monocyclic radical having 5 or 6 ring members and 1-3 hetero atoms which are preferably selected from nitrogen, oxygen and sulfur, especially, for example, thienyl or 2-, 3-or 4-pyridyl, or a bi-or tri-cyclic radical wherein, for example, one or two benzene radicals are annellated (fused) to the mentioned monocyclic radical. In a heterocyclic-aliphatic radical Rio the heterocyclic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially C1-C2 alkyl, which is substituted or preferably unsubstituted.

[001260] Etherified hydroxy is preferably lower alkoxy. Esterified hydroxy is preferably hydroxy esterified by an organic carboxylic acid, such as a lower alkanoic acid, or a mineral acid, such as a hydrohalic acid, for example lower alkanoyloxy or especially halogen, such as iodine, bromine or especially fluorine or chlorine.

[001261] Alkylated amino is, for example, lower alkylamino, such as methylamino, or di-lower alkylamino, such as dimethylamino. Acylated amino is, for example, lower alkanoylamino or benzoylamino.

[001262] Esterified carboxy is, for example, lower alkoxycarbonyl, such as methoxycarbonyl.

[001263] A substituted phenyl radical may carry up to 5 substituents, such as fluorine, but especially in the case of relatively large substituents is generally substituted by only from 1 to 3 substituents. Examples of substituted phenyl that may be given special mention are 4-chloro- phenyl, pentafluoro-phenyl, 2-carboxy-phenyl, 2-methoxy-phenyl, 4-fluorophenyl, 4-cyano- phenyl and 4-methyl-phenyl.

[001264] Salt-forming groups in a compound of formula (I) are groups or radicals having basic or acidic properties. Compounds having at least one basic group or at least one basic radical, for example a free amino group, a pyrazinyl radical or a pyridyl radical, may form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono-or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4- aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane-or 2-hydroxyethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene-or naphthalene-2-sulfonic acid. When several basic groups are present mono-or poly-acid addition salts may be formed.

[001265] Compounds of formula (1) having acidic groups, for example a free carboxy group in the radical Rio, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri- (2-hydroxyethyl)-amine, or heterocyclic bases, for example N-ethylpiperidine or N, N'- dimethyl-piperazine.

Compounds of formula (I) having both acidic and basic groups can form internal salts.

[001266] Of particular interest in these embodiments is a pyrimidine derivative in which Rr is 3- pyridyl, R2, R3, Rs, R6, and R8 are each hydrogen, R4 is methyl, and R7 is a group of formula (II) in which Rg, is hydrogen, X is oxo, k is 0, and Rio is 4- [ (4-methyl-1- piperazinyl) methyl] phenyl. The mesylate salt of this compound having the chemical name 4- [ (4-methyl-1-piperazinyl) methyl]-N [4-methyl-3- [ [4- (3-pyridinyl)-2-pyrimidinyl] amino- phenyl] benzamide methanesulfonate is now commonly known as imatinib mesylate and sold under the trademark GleevecTM.

VEGF antagonists [001267] Suitable VEGF antagonists include, but are not limited to, inhibitors of VEGFR1 tyrosine kinase activity; inhibitors of VEGFR2 tyrosine kinase activity; an antibody to VEGF; an antibody to VEGFR1 ; an antibody to VEGFR2; a ribozyme specific for VEGFR1 or VEGFR2; an antisense specific for VEGFR1 or VEGFR2; siRNA specific for VEGFR1 or VEGFR2; a soluble VEGFR; and the like.

[001268] Exemplary non-limiting VEGF antagonists that are suitable for use in a subject method include, but are not limited to, a compound as disclosed in U. S. Patent no. 6,469, 032 (e. g. , 3- [ (2, 3-Dimethylpyrrol-5-yl) methylene] -2-indolinone, an inhibitor of VEGF-dependent phosphorylation of VEGFR-2 (known as"SU5416" ; see also, Fong et al. (1999) Cancer Res.

59: 99-106); 3- [2, 4-dimethyl-5- (2-oxo-1, 2-dihy- droindol-3-ylidenemethyl)-lH-pyrrol-3- yl] propionic acid (known as"SU6668" ; an inhibitor of VEGFR-2 ; see, e. g. , WO 99/61422; and Laird et al. (2000) Cancer Res. 60: 4152); ZD4190, an inhibitor of VEGFR-1 and VEGFR-2 (see, e. g., Wedge et al. (2000) Cancer Res. 60: 970; and Wedge et al. (2000) Adv. Exp. Med.

Biol. 476: 307-310); [N- (4-bromo-2-fluorophenyl)-6-methoxy-7- [ (l-methylpiperidin-4- yl) methoxy] quinazolin-4-amine] (known as"ZD6474" ; Wedge et al. (2002) Cancer Res.

62: 4645); a 4-anilinoquinazoline compound as disclosed in Hennequin et al. ((2002) J : Med.

Chem. 45 (6): 1300-12); Bevacizumab (AvastinTM), a monoclonal antibody to VEGF; ZM323881 (Whittles et al. (2002) Microcirculation 9: 513-522); PTK787/ZK22584, an inhibitor of VEGFR-1 and VEGFR-2 (Wood et al. (2000) Cancer Res. 60: 2178-2189); AngiozymeTM, an anti-VEGFR-1 ribozyme (Weng et al. (2001) Curr. Oncol. Rep. 3: 141-146); a soluble VEGFR (see, e. g., Takayama et al. (2000) Cancer Res. 60 : 2169-2177; Mori et al.

(2000) Gene Ther. 7: 1027-1033; and Mahasreshti et al. (2001) Clin. Cancer Res. 7: 2057- 2066); a monoclonal antibody to VEGFR-2 (see, e. g., Prewett et al. (1999) Cancer Res.

59: 5209-5218; Witte et al. (1998) Cancer metastasis Rev. 17: 155-161; Brekken et al. (2000) Cancer Res. 60: 5117-5124; Kunkel et al. (2001) Cancer Res. 61: 6624-6628) ; a compound as disclosed in any of U. S. Patent Nos. 5,792, 783,5, 834,504, 5, 883, 113,5, 883,116, 5, 886, 020, 6,225, 335,6, 323,228, and 6,469, 032; a soluble VEGFR as disclosed in U. S. Patent Publication No. 20030181377 ; a compound as disclosed in U. S. Patent Publication No. 20030176487 ; an antibody to VEGFR as disclosed in U. S. Patent Publication No. 20030175271; a compound as disclosed in U. S. Patent Publication No. 20030171378; and the like.

[001269] In some embodiments, a suitable VEGF antagonist is a tyrosine kinase inhibitor that inhibits tyrosine kinase activity of VEGFR1 and/or VEGFR2, but does not substantially inhibit other tyrosine kinases, such as an epidermal growth factor tyrosine kinase. In other embodiments, a suitable VEGF antagonist is a tyrosine kinase inhibitor that inhibits tyrosine kinase activity of VEGFR1 and/or VEGFR2 and only one, two, or three other receptors other than a VEGFR that have tyrosine kinase activity, but does not inhibit tyrosine kinases in general.

[001270] In general, an anti-VEGFR antibody that is suitable for use in a subject method is one that specifically binds a VEGFR (e. g. , VEGFR1 and/or VEGFR2), e. g. , the antibody does not substantially bind to polypeptides that lack one or more epitopes displayed by a VEGFR.

Similarly, an anti-VEGF antibody that is suitable for use herein is one that specifically binds VEGF, e. g. , the antibody binds VEGF but does not substantially bind to polypeptides that lack one or more epitopes displayed by a VEGF. Typically, a specific antibody is one that binds VEGF or a VEGFR with an affinity of at least about 10-7 m/L, at least about 10-8 m/L, at least about 10-9 m/L, or at least about 10-1° m/L or higher.

N-Acetylcysteine (NAC) [001271] N-acetylcysteine (NAC) is a stable form of the sulfur amino acid L-cysteine. NAC is an anti-oxidant that scavenges H202 and other radicals. It is a precursor of glutathione (a major antioxidant), providing cysteine substrate for glutathione synthesis. NAC is commercially available as an over-the-counter nutritional supplement or nutraceutical product.

Suitable NAC products for use herein include the NAC nutritional supplement products made by Source Naturals (1000 mg tablets), Biochem (750 mg tablets), Twinlab (600 mg tablets), Nutricology/Allergy Research Group (500 mg tablets), and the like. Such products can be purchased at minimal cost from health food stores and nutritional supplement retailers, such as General Nutrition Center (GNC).

Side effect management agents [001272] In some embodiments, a subject therapy comprises administering a palliative agent (e. g. , an agent that reduces patient discomfort caused by a therapeutic agent), or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent. Such agents are also referred to as"side effect management agents." [001273] Suitable side effect management agents include agents that are effective in pain management; agents that ameliorate gastrointestinal discomfort ; analgesics, anti- inflammatories, antipsychotics, antineurotics, anxiolytics, and hematopoietic agents. In addition, the invention contemplates the use of any compound for palliative care of patients suffering from pain or any other side effect in the course of treatment with a subject therapy.

Exemplary palliative agents include acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

[001274] Analgesics that can be used to alleviate pain in the methods of the invention include non-narcotic analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen, salicylate, acetyl-salicylic acid (aspirin, diflunisal), ibuprofen, Motrin, Naprosyn, Nalfon, and Trilisate, indomethacin, glucametacine, acemetacin, sulindac, naproxen, piroxicam, diclofenac, benoxaprofen, ketoprofen, oxaprozin, etodolac, ketorolac tromethamine, ketorolac, nabumetone, and the like, and mixtures of two or more of the foregoing.

[001275] Other suitable analgesics include fentanyl, buprenorphine, codeine sulfate, morphine hydrochloride, codeine, hydromorphone (Dilaudid), levorphanol (Levo-Dromoran), methadone (Dolophine), morphine, oxycodone (in Percodan), and oxymorphone (Numorphan). Also suitable for use are benzodiazepines including, but not limited to, flurazepam (Dalmane), diazepam (Valium), and Versed, and the like.

Anti-inflammatory agents [001276] Suitable anti-inflammatory agents include, but are not limited to, steroidal anti- inflammatory agents, and non-steroidal anti-inflammatory agents.

[001277] Suitable steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, conisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures of two or more of the foregoing.

[001278] Suitable non-steroidal anti-inflammatory agents, include, but are not limited to, 1) the oxicams, such as piroxicam, isoxicam, tenoxicam, and sudoxicam; 2) the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; 3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; 4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and 6) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone, mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceutically-acceptable salts and esters of these agents.

79] Suitable anti-inflammatory agents include, but are not limited to, Alclofenac ; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen ; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone;-Dexamethasone Dipropionate ; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate;-Diflumidone Sodium ; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac ; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac ; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole ; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen ; Lofemizole Hydrochloride; Lornoxicam ; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone ; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate ; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam ; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium ; Tenoxicam; Tesicam ; Tesimide; Tetrydamine; Tiopinac ; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium.

[001280] Antipsychotic and antineurotic drugs that can be used to alleviate psychiatric side effects in the methods of the invention include any and all selective serotonin receptor inhibitors (SSRIs) and other anti-depressants, anxiolytics (e. g. alprazolam), etc. Anti- depressants include, but are not limited to, serotonin reuptake inhibitors such as Celexa#, Desyrel, Effexor&commat;, Luvox&commat;, Paxil (R), Prozac&commat;, Zoloft&commat;, and Serzone ; tricyclics such as Adapin&commat;, Anafrinil#, Elavil#, Janimmine#, Ludiomil#, Pamelor#, Tofranil#, Vivactil#, Sinequan (k, and Surmontil ; monoamine oxidase inhibitors such as Eldeprylg, Marplan, Nardilg, and Parnate&commat;. Anti-anxiety agents include, but are not limited to, azaspirones such as BuSpar#, benzodiazepines such as Ativan (t, LibriumX), Tranxene (g), Cenkax (g), Klonopin (g), PaxipamO, Seraxg, Valiumg, and Xanax ; and beta-blockers such as Inderal (D and Tenormin#.

[001281] Agents that reduce gastrointestinal discomfort such as nausea, diarrhea, gastrointestinal cramping, and the like are suitable palliative agents for use in a subject combination therapy.

Suitable agents include, but are not limited to, antiemetics, anti-diarrheal agents, H2 blockers, antacids, and the like.

[001282] Suitable H2 blockers (histamine type 2 receptor antagonists) that are suitable for use as a palliative agent in a subject therapy include, but are not limited to, Cimetidine (e. g., Tagamet, Peptol, Nu-cimet, apo-cimetidine, non-cimetidine); Ranitidine (e. g., Zantac, Nu-ranit, Novo- randine, and apo-ranitidine); and Famotidine (Pepcid, Apo-Famotidine, and Novo-Famotidine).

[001283] Suitable antacids include, but are not limited to, aluminum and magnesium hydroxide (Maalox&commat;, Mylanta&commat;) ; aluminum carbonate gel (Basajel&commat;) ; aluminum hydroxide (Amphojel0, AlternaGEL) ; calcium carbonate (Tumse, Titralacg) ; magnesium hydroxide; and sodium bicarbonate.

[001284] Antiemetics include, but are not limited to ; 5-hydroxytryptophan-3 (5HT3) inhibitors; corticosteroids such as dexamethasone and methylprednisolone; Marinol# (dronabinol) ; prochlorperazine; benzodiazepines; promethazine; and metoclopramide cisapride; Alosetron Hydrochloride; Batanopride Hydrochloride; Bemesetron; Benzquinamide ; Chlorpromazine; Chlorpromazine Hydrochloride; Clebopride; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate ; Dolasetron Mesylate; Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron Hydrochloride; Granisetron ; Granisetron Hydrochloride; Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopramide Hydrochloride ; Metopimazine; Ondansetron Hydrochloride; Pancopride ; Prochlorperazine; Prochlorperazine Edisylate; Prochlorperazine Maleate; Promethazine Hydrochloride; Thiethylperazine; Thiethylperazine Malate; Thiethylperazine Maleate; Trimethobenzamide Hydrochloride; Zacopride Hydrochloride..

[001285] Anti-diarrheal agents include, but are not limited to, Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine), and the like.

[001286] Suitable hematopoietic agents that can be used to prevent or restore depressed blood cell populations in the methods of the invention include erythropoietins, such as EPOGEN epoetin-alfa, granulocyte colony stimulating factors (G-CSFs), such as NEUPOGENTM filgrastim, granulocyte-macrophage colony stimulating factors (GM-CSFs), thrombopoietins, etc.

DOSAGES, FORMULATIONS, AND ROUTES OF ADMINISTRATION [001287] Active agents (e. g. , a Type I interferon receptor agonist, a Type II interferon receptor agonist, pirfenidone, a TNF antagonist, a SAPK inhibitor, a VEGF antagonist, a TGF-P antagonist, etc. ) are generally administered to individuals in formulations admixed with a pharmaceutically acceptable excipient (s). A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington : The Science and Practice of Pharmacy,"20th edition, Lippincott, Williams, & Wilkins ; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H. C. Ansel et al., eds. j 7th ed. , Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A. H. Kibbe et al. , eds., 3ded. Amer. Pharmaceutical Assoc.

[001288] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

[001289] In the subject methods, the active agents may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agents can be incorporated into a variety of formulations for therapeutic administration. More particularly, the agents of the present invention can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

[001290] As such, administration of the agents can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc., administration. In some embodiments, two different routes of administration are used. For example, in some embodiments, IFN-y is administered subcutaneously, while pirfenidone is administered orally.

[001291] Subcutaneous administration of an active agent (e. g. , a Type I interferon receptor agonist, a Type II interferon receptor agonist, pirfenidone, a TNF antagonist, a SAPK inhibitor, a VEGF antagonist, a TGF-ß antagonist, etc. ) is accomplished using standard methods and devices, e. g. , needle and syringe, a subcutaneous injection port delivery system, and the like.

See, e. g. , U. S. Patent Nos. 3,547, 119; 4,755, 173; 4,531, 937; 4,311, 137; and 6,017, 328. A combination of a subcutaneous injection port and a device for administration of an interferon receptor agonist to a patient through the port is referred to herein as"a subcutaneous injection port delivery system. "In some embodiments, subcutaneous administration is achieved by a combination of devices, e. g. , bolus delivery by needle and syringe, followed by delivery using a continuous delivery system.

[001292] In some embodiments, an active agent (e. g. , a Type I interferon receptor agonist, a Type II interferon receptor agonist, pirfenidone, a TNF antagonist, a SAPK inhibitor, a VEGF antagonist, a TGF-, B antagonist, etc. ) is delivered by a continuous delivery system. The term "continuous delivery system"is used interchangeably herein with"controlled delivery system" and encompasses continuous (e. g. , controlled) delivery devices (e. g. , pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.

[001293] Mechanical or electromechanical infusion pumps can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U. S. Pat.

Nos. 4,692, 147; 4,360, 019; 4,487, 603; 4,360, 019; 4,725, 852; 5,820, 589; 5,643, 207; 6,198, 966; and the like. In general, the present methods of drug delivery can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. Typically, the agent (e. g. , a Type I interferon receptor agonist, e. g., IFN-a ; or a Type II interferon receptor agonist, e. g., IFN-y) is in a liquid formulation in a drug-impermeable reservoir, and is delivered in a continuous fashion to the individual.

[001294] In one embodiment, the drug delivery system is an at least partially implantable device.

The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. An implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are generally preferred because of convenience in implantation and removal of the drug delivery device.

[001295] Drug release devices suitable for use in the invention may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e. g. , an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e. g., where the drug is incorporated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e. g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drug release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc.

[001296] Drug release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U. S. Pat. Nos. 4,692, 147; 4,360, 019; 4,487, 603; 4,360, 019; 4,725, 852, and the like. In general, the present methods can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems are generally preferred due to their generally more consistent, controlled release over time.

Osmotic pumps are particularly preferred due to their combined advantages of more consistent controlled release and relatively small size (see, e. g. , PCT published application no. WO 97/27840 and U. S. Pat. Nos. 5,985, 305 and 5,728, 396) ). Exemplary osmotically-driven devices suitable for use in the invention include, but are not necessarily limited to, those described in U. S. Pat. Nos. 3,760, 984; 3,845, 770; 3,916, 899; 3,923, 426; 3,987, 790; 3,995, 631 ; 3,916, 899; 4,016, 880; 4,036, 228; 4,111, 202; 4,111, 203; 4,203, 440; 4,203, 442; 4,210, 139; 4,327, 725; 4,627, 850; 4, 865, 845 ; 5,057, 318; 5,059, 423; 5,112, 614 ; 5,137, 727; 5,234, 692; 5,234, 693; 5,728, 396; and the like.

[001297] In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in the art. As noted infra, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body.

[001298] In some embodiments, an active agent (e. g. , a Type I interferon receptor agonist, a Type II interferon receptor agonist, pirfenidone, a TNF antagonist, a SAPK inhibitor, a VEGF antagonist, a TGF-P antagonist, etc. ) is delivered using an implantable drug delivery system, e. g. , a system that is programmable to provide for administration of the agent. Exemplary programmable, implantable systems include implantable infusion pumps. Exemplary implantable infusion pumps, or devices useful in connection with such pumps, are described in, for example, U. S. Pat. Nos. 4,350, 155; 5,443, 450; 5,814, 019; 5,976, 109; 6,017, 328; 6,171, 276; 6,241, 704; 6,464, 687; 6, 475,180 ; and 6,512, 954. A further exemplary device that can be adapted for the present invention is the Synchromed infusion pump (Medtronic).

[001299] In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.

[001300] For oral preparations, the agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose ; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[001301] The agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[001302] Furthermore, the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. An active agent can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

[001303] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more active agents. Similarly, unit dosage forms for injection or intravenous administration may comprise the agent (s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.

[001304] The term"unit dosage form,"as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of an active agent-calculated in an-amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the dosage form depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat proliferative disorders [001305] In some embodiments, a subject method for treating a proliferative disorder comprises administering effective amounts of a Type II interferon receptor agonist and a Type I interferon receptor agonist.

[001306] In some embodiments, at least one dose of a Type II interferon receptor agonist is administered concurrently with at least one dose of a Type I interferon receptor agonist. As used herein, the term"concurrently"indicates that the Type II interferon receptor agonist and the Type I interferon receptor agonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[001307] In some embodiments, a Type II interferon receptor agonist is administered during the entire course of Type I interferon receptor agonist treatment. In other embodiments, a Type II interferon receptor agonist is administered for a period of time that is overlapping with that of the Type I interferon receptor agonist treatment, e. g. , the Type II interferon receptor agonist treatment can begin before the Type I interferon receptor agonist treatment begins and end before the Type I interferon receptor agonist treatment ends; the Type II interferon receptor agonist treatment can begin after the Type I interferon receptor agonist treatment begins and end after the Type II interferon receptor agonist treatment ends; the Type II interferon receptor agonist treatment can begin after the Type I interferon receptor agonist treatment begins and end before the Type I interferon receptor agonist treatment ends; or the Type II interferon receptor agonist treatment can begin before the Type I interferon receptor agonist treatment begins and end after the Type I interferon receptor agonist treatment ends.

[001308] In connection with each of the methods described herein, the invention provides embodiments in which the Type I interferon receptor agonist and/or a Type II interferon receptor agonist is administered to the patient by a controlled drug delivery device. In some embodiments, the Type I interferon receptor agonist and/or a Type II-interferon receptor agonist is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the Type I interferon receptor agonist and/or a Type II interferon receptor agonist to the patient substantially continuously or continuously by subcutaneous infusion.

[001309] In other embodiments, the Type I interferon receptor agonist and/or a Type II interferon receptor agonist is/are administered to the patient so as to achieve and maintain a desired average daily serum concentration of the Type I interferon receptor agonist and/or a Type II interferon receptor agonist at a substantially steady state for the duration of the Type I interferon receptor agonist and/or a Type II interferon receptor agonist therapy. Optionally, an implantable infusion pump is used to deliver the Type I interferon receptor agonist and/or a Type II interferon receptor agonist to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the Type I interferon receptor agonist and/or a Type II interferon receptor agonist at a substantially steady state for the duration of the Type I interferon receptor agonist and/or a Type II interferon receptor agonist therapy.

[001310] A Type II interferon receptor agonist can be administered daily, twice daily, every other day, twice a week, three times a week, or substantially continuously or continuously.

Effective dosages of a Type II interferon receptor agonist can range from about 1 llg to about 1000 ug.

[001311] In some embodiments, the Type II interferon receptor agonist is IFN-gamma. Effective dosages of IFN-gamma range from about 0.5 pg/m2 to about 500 llg/m2, usually from about 1.5 llg/m2 to 200 pg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 pLg of protein. IFN-gamma can be administered daily, every other day, three times a week, or substantially continuously or continuously.

[001312] In specific embodiments of interest, IFN-gamma is administered to an individual in a unit dosage form of from about 25 llg to about 500 ug, from about 50 ug to about 400 ag, or from about 100 ug to about 300 u. g. In particular embodiments of interest, the dose is about 200 Rg IFN-gamma. In many embodiments of interest, IFN-ylb is administered. Where the dosage is 200 µg IFN-gamma per dose, the amount of IFN-gamma per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 , ug IFN-gamma per kg body weight to about 1. 48 gag IFN-gamma per kg body weight.

[001313] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-gamma dosage ranges from about 150 pLg/m2 to about 20 µg/m2. For example, an IFN-y dosage ranges from about 20 µg/m2 to about 30 µg/m2, from about 30 ug/m2 to about 40 µg/m2, from about 40 Fg/m2 to about 50 µg/m2, from about 50 µg/m2 to about 60 µg/m2, from about 60, ug/m2 to about 70, ug/m2, from about 70 µg/m2 to about 80 µg/m2, from about 80 µg/m2 to about 90 µg/m2, from about 90, ug/m2 to about 100 µg/m2, from about 100 µg/m2 to about 110 µg/m2, from about 110 µg/m2 to about 120 µg/m2, from about 120 pg/m2 to about 130 µg/m2, from about 130 µg/m2 to about 140 Zg/m2, or from about 140, ug/m2 to about 150 µg/m2. In some embodiments, the dosage groups range from about 25 µg/m2 to about 100 ug/m2. In other embodiments, the dosage groups range from about 25 µg/m2 to about 50 µg/m2.

[001314] A Type I or a Type II interferon receptor agonist can be administered twice daily, daily, every other day, once a week, twice a week, three times a week, every other week, three times per month, or once monthly, substantially continuously or continuously.

[001315] In some embodiments, the Type I interferon receptor agonist is an IFN-alpha. Effective dosages of an IFN-alpha range from about 3 ug to about 27 µg, from about 3 MU to about 10 MU, from about 90 llg to about 180 u. g, or from about 18 wu to about 90 µg.

[001316] Effective dosages of Infergen# consensus IFN-alpha include about 3 µg, about 6 µg, about 9 gag, about 12 µg, about 15 u. g, about 18 u. g, about 21 gg, about 24 u. g, about 27 µg, or about 30 µg, of drug per dose. Effective dosages of IFN-a2a and IFN-a2b can contain an amount of about 3 million Units (MU) to about 30 MU of drug per dose. Effective dosages of PEGASYS#PEGylated IFN-a2a can contain an amount of about 5 llg to about 500 µg, or about 45 ug to about 450 µg, or about 60 llg to about 400 u, g, or about 75 ug to about 350 gag, or about 90 llg to about 300 u. g, about 105 llg to about 270 µg, or about 120 µg to about 240 u. g, or about 135 u. g to about 210 u. g, or about 150 ug to about 180 gg, or about 135 Rg, of drug per dose.

[001317] Effective dosages of PEG-INTRON&commat;PEGylated IFN-a2b can contain an amount of about 0. 5 µg to about 5.0 µg, or about 0. 75 ig to about 3. 5 µg, or about 1. zug to about 3.0 gg, or about 1. 25 ug to about 2.5 u. g, or about 1. 5 wu to about 2. 0 µg, of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 9 u. g to about 200 gg, or about 12 ug to about 180 µg, or about 15 g to about 150 ug, or about 18 ug to about 120 ug, or about 21 llg to about 90 ug, or about 24 , ug to about 75 ug, or about 27 ug to about 60 ug, or about 45 ug, of CIFN amino acid weight per dose of PEG-CIFN. Effective dosages of monoPEG (30 kD, linear) -ylated CIFN can contain an amount of about 5 fig to about 500 ug, or about or about 45 pLg to about 450 ug, or about 60 llg to about 400 ug, or about 75 llg to about 350 ug, or about 90 llg to about 300 ug, about 105 ug to about 270 Rg, or about 120 gag to about 240 ug, or about 135 Zg to about 210 µg, or about 150 µg to about 180 ug, or about 135 ug, of drug per dose.

[001318] IFN-a can be administered daily, every other day, once a week, twice a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[0013191 In some embodiments, a Type I or a Type II interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen. The first dosing regimen of Type I or a Type II interferon receptor agonist (also referred to as"the induction regimen") generally involves administration of a higher dosage of the Type I interferon receptor agonist.

For example, in the case of Infergen consensus IFN-alpha (CIFN), the first dosing regimen comprises administering CIFN at about 9 ug, about 15 ug, about 18 lug, or about 27 ug. The first dosing regimen can encompass a single dosing event, or at least two or more dosing events. The first dosing regimen of the Type I interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously. The first dosing regimen of the Type I interferon receptor agonist is administered for a first period of time, which time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.

[001320] The second dosing regimen of the Type I interferon receptor agonist (also referred to as "the maintenance dose") generally involves administration of a lower amount of the Type I interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CIFN at a dose of at least about 3 pLg, at least about 9 ug, at least about 15 µg, or at least about 18 µg. The second dosing regimen can encompass a single dosing event, or at least two or more dosing events.

[001321] The second dosing regimen of the Type I interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001322] In some embodiments, where an"induction"/"maintenance"dosing regimen of a Type I interferon receptor agonist is administered, a"priming"dose of a Type II interferon receptor agonist (e. g., IFN-gamma) is included. In these embodiments, IFN-gamma is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I interferon receptor agonist. This period of time is referred to as the"priming"phase. In some of these embodiments, the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I interferon receptor agonist. In these embodiments, the total time of treatment with Type II interferon receptor agonist (including the"priming"phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days. In still other embodiments, the Type II interferon receptor agonist treatment is discontinued once Type I interferon receptor agonist treatment begins.

[001323] In other embodiments, the Type I interferon receptor agonist is administered in a single dosing regimen. For example, in the case of CIFN, the dose of CIFN is generally in a range of from about 3 llg to about 15 pLg, or from about 9 llg to about 15 ug. The dose of Type I interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times per month, once monthly, or substantially continuously. The dose of the Type I interferon receptor agonist is administered for a period of time, which period can be, for example, from at least about 24 weeks to at least about 48 weeks, or longer.

[001324] In some embodiments, where a single dosing regimen of a Type I interferon receptor agonist is administered, a"priming"dose of a Type II interferon receptor agonist (e. g. , IFN- gamma) is included. In these embodiments, IFN-gamma is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I interferon receptor agonist.

This period of time is referred to as the"priming"phase. In some of these embodiments, the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I interferon receptor agonist. In these embodiments, the total time of treatment with the Type II interferon receptor agonist (including the"priming"phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days. In still other embodiments, Type II interferon receptor agonist treatment is discontinued once Type I interferon receptor agonist treatment begins.

[001325] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means., [001326] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[001327] In some embodiments, the Type I interferon receptor agonist and a Type II interferon receptor agonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the Type I interferon receptor agonist and a Type II interferon receptor agonist are administered separately, e. g. , in separate formulations. In some of these embodiments, the Type I interferon receptor agonist and a Type II interferon receptor agonist are administered separately, and are administered simultaneously. In other embodiments, the Type I interferon receptor agonist and a Type II interferon receptor agonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[001328] Multiple doses of Type I interferon receptor agonist and a Type II interferon receptor agonist can be administered, e. g. , the Type I interferon receptor agonist and a Type II interferon receptor agonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001329] In some embodiments, IFN-alpha and IFN-gamma are co-formulated, for example, in a single liquid formulation that is contained in a single reservoir, for use in a drug delivery device. Thus, the present invention provides a pharmaceutical formulation comprising a single dose of IFN-alpha and a single dose of IFN-gamma sufficient for use in any method described herein that employs the co-administration of IFN-alpha and IFN-gamma in the treatment of a patient. In some aspects, the present invention provides a drug reservoir or other container containing IFN-alpha and IFN-gamma co-formulated in a liquid, wherein both IFN-alpha and IFN-gamma are present in the formulation in an amount suitable for one dose each. Dosage amounts are described herein. The reservoir can be provided in any of a variety of forms, including, but not limited to, a cartridge, a syringe, a reservoir of a continuous delivery device, and the like. The invention further provides a drug delivery device comprising (e. g. , pre- loaded with) a reservoir containing a liquid formulation that comprises a single dose of IFN- alpha and a single dose of IFN-gamma. Exemplary, non-limiting drug delivery devices include injection devices, such as pen injectors, needle/syringe devices, continuous delivery devices, and the like. Any of the dosage amounts, including synergistically effective amounts, described herein can be used in the pharmaceutical formulation, in the reservoir, or in the drug delivery device.

[001330] In other embodiments, where IFN-alpha and IFN-gamma are administered in combination therapy, the IFN-alpha and IFN-gamma are in separate pharmaceutical formulations contained in separate reservoirs in the same drug delivery device. The invention further provides a drug delivery device that is pre-loaded with separate reservoirs, one reservoir containing a liquid formulation comprising a single dose of IFN-alpha, and a second reservoir containing a liquid formulation comprising a single dose of IFN-gamma. Any of the dosage amounts, including synergistically effective amounts, described herein can be used in the pharmaceutical formulations, the reservoirs, or in the drug delivery device.

[001331] In some embodiments, in a treatment method described herein, the subject method comprises administering to the patient an effective amount of a Type I interferon receptor agonist that is an IFN-alpha, and the subject method further comprises co-administering to the patient an effective amount of IFN-gamma for the duration of the IFN-alpha therapy. In one embodiment, the IFN-gamma is administered to the patient by bolus injection. In another embodiment, the IFN-alpha and IFN-gamma are administered to the patient by a drug delivery device. Optionally, the device is used to deliver the IFN-alpha to the patient by substantially continuous or continuous administration and used to deliver the IFN-gamma to the patient by bolus administration tiw, biw, qod, or qd. Optionally, the device is used to deliver the IFN- alpha and IFN-gamma to the patient in the same manner and pattern of administration, such as substantially continuous or continuous administration. Optionally, the IFN-alpha and IFN- gamma are contained in separate reservoirs in the drug delivery device. Optionally, the IFN- alpha and IFN-gamma are co-formulated in a single liquid formulation that is contained in a single reservoir in the drug delivery device.

[001332] Where the agent is a polypeptide, polynucleotide (e. g. , a polynucleotide encoding a Type I interferon receptor agonist or a Type II interferon receptor agonist), it may be introduced into tissues or host cells by any number of routes, including viral infection, microinjection, or fusion of vesicles. Jet injection may also be used for intramuscular administration, as described by Furth et aL, 1992, Anal. Biochem. 205: 365-368. The DNA may be coated onto gold microparticles, and delivered intradermally by a particle bombardment device, or"gene gun"as described in the literature (see, for example, Tang et al., 1992, Nature 356: 152-154), where gold microprojectiles are coated with the therapeutic DNA, then bombarded into skin cells. la. Type II interferon receptor agonist, Type I interferon receptor agonist, and an additional therapeutic agent in combination therapy to treat proliferative disorders [001333] Any of the above-described interferon treatments can be used in conjunction with administration of an additional therapeutic agent (s), e. g. , a specific anti-cancer, anti- angiogenic, or anti-fibrotic agent that is effective in treating a disease.

[001334] In some embodiments, the method further includes administration of pirfenidone or a pirfenidone analog. Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001335] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/lcg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos., 5,310, 562; 5,518, 729; 5,716, 632; and 6,090, 822.

[001336] In some embodiments, pirfenidone or a pirfenidone analog is administered throughout the entire course of Type I interferon receptor agonist and/or Type II interferon receptor agonist treatment. In other embodiments, pirfenidone or a pirfenidone analog is administered less than the entire course of Type I interferon receptor agonist and/or Type II interferon receptor agonist treatment, for example, only during a first phase of Type I interferon receptor agonist and/or Type II interferon receptor agonist treatment, only during a second phase of Type I interferon receptor agonist and/or Type II interferon receptor agonist treatment, or some other portion of the Type I interferon receptor agonist and/or Type II interferon receptor agonist treatment regimen.

2) Type II interferon receptor agonist, SAPK inhibitor, and third therapeutic agent in combination therapy for treating proliferative disorders [001337] In connection with each of the methods described herein, the invention provides embodiments in which the active agent (s) (e. g. , a Type II interferon receptor agonist and/or SAPK inhibitor) is/are administered to the patient by a controlled drug delivery device. In some embodiments, the Type II interferon receptor agonist and/or SAPK inhibitor is/are delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the Type II interferon receptor agonist and/or SAPK inhibitor to the patient substantially continuously or continuously by subcutaneous infusion.

[001338] In other embodiments, the-Type II interferon receptor agonist and/or SAPK inhibitor is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the Type II interferon receptor agonist and/or SAPK inhibitor at a substantially steady state for the duration of the Type II interferon receptor agonist and/or SAPK inhibitor therapy. Optionally, an implantable infusion pump is used to deliver the Type II interferon receptor agonist and/or SAPK inhibitor to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the Type II interferon receptor agonist and/or SAPK inhibitor at a substantially steady state for the duration of the Type II interferon receptor agonist and/or SAPK inhibitor therapy.

[001339] In some embodiments, the Type II interferon receptor agonist is an IFN-y.

[001340] Effective dosages of IFN-y can range from about 0. 5 pg/m2 to about 500 pg/m2, usually from about 1.5 llg/m2 to 200 Fg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 u. g of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously.

[001341] In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 llg to about 500 lug, from about 50 u. g to about 400 ug, or from about 100 ug to about 300 u, g. In particular embodiments of interest, the dose is about 200 Zg IFN-y. In many embodiments of interest, IFN-ylb is administered.

[001342] Where the dosage is 200 u, g IFN-y per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4. 4 µg IFN-&gamma; per kg body weight to about 1.48 1lg IFN-per kg body weight.

[001343] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 llg/m2 to about 20 µg/m2. For example, an IFN-y dosage ranges from about 20 llg/m2 to about 30, ug/m2, from about 30 µg/m2 to about 40 Rg/m2, from about 40 µg/m2 to about 50 ug/m2, from about 50 µg/m2 to about 60 µg/m2, from about 60 µg/m2 to about 70 µg/m2, from about 70 Rg/m2 to about 80 llg/m2, from about 80 µg/m2 to about 90 µg/m2, from about 90 zg/m2 to about 100 µg/m2, from about 100 llg/m2 to about 110 µg/m2, from about 110 µg/m2 to about 120 µg/m2, from about 120 llg/m2 to about 130 0 gg/m2, from about 130 u-g/m to about 140 µg/m2, or from about 140 ug/m2 to about 150, ug/m2. In some embodiments, the dosage groups range from about 25 µg/m2 to about 100 µg/m2. In other embodiments, the dosage groups range from about 25 µg/m2 to about 50 µg/m2.

[001344] In many embodiments, IFN-&gamma; is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.

IFN-y can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[001345] In many embodiments, multiple doses of an IFN-y are administered. For example, an IFN-y is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001346] Effective dosages of a SAPK inhibitor range from about 0.1 u. g to about 3600 mg per dose, e. g., from about 0. 1 gag to about 0. 5 u, g per dose, from about 0.5 llg to about 1. 0 ug per dose, from about 1. 0 ug per dose to about 5.0 vag per dose, from about 5.0 llg to about 10 pg per dose, from about 10 u, g to about 20 u. g per dose, from about 20 u. g per dose to about 30 0 gag per dose, from about 30 Rg per dose to about 40 u. g per dose, from about 40 Rg per dose to about 50 llg per dose, from about 50 llg per dose to about 60 u, g per dose, from about 60 u, g per dose to about 70 llg per dose, from about 70 Zg to about 80 ug per dose, from about 80 llg per dose to about 100 Uug per dose, from about 100 Ag to about 150 llg per dose, from about 150 u. g to about 200 ug per dose, from about 200 u. g per dose to about 250 gag per dose, from about 250 llg to about 300 llg per dose, from about 300 u. g to about 400 pg per dose, from about 400 jig to about 500 u. g per dose, from about 500 ug to about 600 llg per dose, from about 600 ug to about 700 llg per dose, from about 700 u. g to about 800 ug per dose, from about 800 u, g to about 900 ßg per dose, from about 900 sug to about 1000 wu per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, from about 35 mg to about 40 mg per dose, from about 40 mg to about 100 mg per dose, from about 100 mg to about 400 mg per dose, from about 400 mg to about 1000 mg per dose, from about 1000 mg per dose to about 1500 mg per dose, from about 1500 mg per dose to about 2000 mg per dose, from about 2000 mg per dose to about 3000 mg per dose, or from about 3000 mg per dose to about 3600 mg per dose.

[001347] In many embodiments, a SAPK inhibitor is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The SAPK inhibitor can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[001348] In many embodiments, multiple doses of a SAPK inhibitor are administered. For example, a SAPK inhibitor is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001349] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[001350] In some embodiments, a SAPK inhibitor is administered throughout the entire course of Type II interferon receptor agonist treatment. In other embodiments, a SAPK inhibitor is administered less than the entire course of Type II interferon receptor agonist treatment, e. g., only during the first phase of Type II interferon receptor agonist treatment, only during the second phase of Type II interferon receptor agonist treatment, or some other portion of the Type II interferon receptor agonist treatment regimen.

[001351] In some embodiments, a SAPK inhibitor is pirfenidone or a pirfenidone analog.

Effective dosages of pirfenidone or a specific pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos. , 5,310, 562 ; 5,518, 729 ; 5,716, 632 ; and 6,090, 822.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat proliferative disorders [001352] In connection with each of the methods described herein, the invention provides embodiments in which a therapeutic agent is administered to the patient by a controlled drug delivery device. In some embodiments, a therapeutic agent is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver a therapeutic agent to the patient substantially continuously or continuously by subcutaneous infusion.

[001353] In other embodiments, a therapeutic agent is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the combination therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the combination therapy.

Type II interferon receptor agonists [001354] In some embodiments, the Type II interferon receptor agonist is an IFN-&gamma;. In some of these embodiments, the IFN-y is Actimmune human IFN-&gamma;1b.

[001355] Effective dosages of IFN-y can range from about 0.5 µg/m2 to about 500 µg/m2, usually from about 1.5 pg/m2 to 200 µg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 u. g of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously.

[001356] In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 ug to about 500 ug, from about 50 ug to about 400 gag, or from about 100 ug to about 300 µg. In particular embodiments of interest, the dose is about 200 llg IFN-Y. In many embodiments of interest, IFN-&gamma;1b is administered.

[001357] Where the dosage is 200 µg IFN-&gamma; per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4. 4 µg IFN-&gamma; per kg body weight to about 1.48 µg IFN-&gamma; per kg body weight.

[001358] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 ug/m2 to about 20 ug/m2. For example, an IFN-y dosage ranges from about 20 ug/m2 to about 30 µg/m2, from about 30 ug/m2 to about 40 llg/m2, from about 40 llg/m2 to about 50, ug/m2, from about 50 , ug/m2 to about 60 Fg/m2, from about 60, ug/m2 to about 70 llg/m2, from about 70 Zg/m2 to about 80 µg/m2, from about 80 µg/m2 to about 90 µg/m2 from about 90 pg/m2 to about 100 µg/m2, from about 100 µg/m2 to about 110 µg/m2, from about 110 µg/m2 to about 120 µg/m2, from about 120 µg/m2 to about 130 µg/m2, from about 130, ug/m2 to about 140, ug/m2, or from about 140, ug/m2 to about 150 µg/m2. In some embodiments, the dosage groups range from about 25 µg/m2 to about 100 µg/m2. In other embodiments, the dosage groups range from about 25 Rg/m2 to about 50 µg/m2.

[001359] In some embodiments, the IFN-y is Actimmune human IFN-ylb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 u. g, 50 ug, 100 ug, 150 ug, or 200 µg.

VEGF antagonists [001360] Effective dosages of a VEGF antagonist range from about 10 mg to about 1500 mg per dose, e. g., from about 10 mg per dose to about 25 mg per dose, from about 25 mg per dose to about to about 50 mg per dose, from about 50 mg to about 75 mg per dose, from about 75 mg to about 100 mg per dose, from about 100 mg per dose to about 150 mg per dose, from about 150 mg per dose to about 200 mg per dose, from about 200 mg per dose to about 250 mg per dose, from about 250 mg per dose to about 300 mg per dose, from about 300 mg per dose to about 350 mg per dose, from about 350 mg per dose to about 400 mg per dose, from about 400 mg per dose to about 450 mg per dose, from about 450 mg per dose to about 500 mg per dose, from about 500 mg per dose to about 600 mg per dose, from about 600 mg per dose to about 700 mg per dose, from about 700 mg per dose to about 800 mg per dose, from about 800 mg per dose to about 900 mg per dose, from about 900 mg per dose to about 1000 mg per dose, from about 1000 mg per dose to about 1100 mg per dose, from about 1100 mg per dose to about 1200 mg per dose, from about 1200 mg per dose to about 1300 mg per dose, from about 1300 mg per dose to about 1400 mg per dose, or from about 1400 mg per dose to about 1500 mg per dose.

[001361] In some embodiments, effective dosages of a VEGF antagonist are expressed as mg per body surface area (mg/m2). In these embodiments, effective dosages of a VEGF antagonist are from about 10 mg/m2 to about 500 mg/m2, e. g., from about 10 mg/m2 to about 25 mg/m2, from about 25 mg/m2 to about 50 mg/m2, from about 50'mg/m2 to about 75 mg/m2, from about 75 mg/m2 to about 100 mg/m2, from about 100 mg/m2 to about 125 mg/m2, from about 125 mg/m2 to about 150 mg/m2, from about 150 mg/m2 to about 175 mg/m2, from about 175 mg/m2 to about 200 mg/m2, from about 225 mg/m2, from about 225 mg/m2 to about 250 mg/m2, from about 250 mg/m2 to about 300 mg/m2, from about 300 mg/in2 to about 350 mg/m2, from about 350 mg/m2 to about 400 mg/m2, from about 400 mg/m2 to about 450 mg/m2, or from about 450 mg/m2 to about 500 mg/m2.

[001362] In some embodiments, effective dosages of a VEGF antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 5 mg/kg body weight to about 200 mg/kg body weight, e. g., from about 5.0 mg/kg body weight to about 10 mg/kg body weight, from about 10 mg/kg body weight to about 15 mg/kg body weight, from about 15 mg/kg body weight to about 25 mg/kg body weight, from about 25 mg/kg body weight to about 50 mg/kg body weight, from about 50 mg/kg body weight to about 75 mg/kg body weight, from about 75 mg/kg body weight to about 100 mg/kg body weight, from about 100 mg/kg body weight to about 125 mg/kg body weight, from about 125 mg/kg body weight to about 150 mg/kg body weight, or from about 150 mg/kg body weight to about 200 mg/kg body weight.

[001363] Exemplary, non-limiting VEGF antagonists that are administered in a subject combination therapy are SU5416, SU6668, ZD4190, ZD6474, Avastin monoclonal antibody, ZM323881, PTK787/ZK22584, and AngioZyMeTm anti VEGFR ribozyme.

[001364] In many embodiments, a VEGF antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time (e. g. , 2 years, 3 years, or longer). The VEGF antagonist can be administered three times a day (tid), twice a day (bid), daily (qd), every other day (qod), twice per week (biw), three times per week (tiw), once per week (qw), every other week (qow), three times per month, once every 21 days, once monthly, substantially continuously, or continuously.

[001365] In some embodiments, the VEGF antagonist is SU 6668, and is administered orally twice daily (bid) at a dosage of from about 50 mg/m2 to about 500 mg/m2, e. g., from about 50 mg/m2 to about 75 mg/m2, from about 75 mg/m2 to about 100 mg/m2, from about 100 mg/m2 to about 125 mg/m2, from about 125 mg/m2 to about 150 mg/m2, from about 150 mg/m2 to about 200 mg/m2, from about 200 mg/m2 to about 250 mg/m2, from about 250 mg/m2 to about 300 mg/m2, from about 300 mg/m2 to about 350 mg/m2, from about 350 mg/m2 to about 400 mg/m2, from about 400 mg/m2 to about 450 mg/m2, or from about 450 mg/m2 to about 500 mg/m2. In a particular embodiment, SU 6668 is administered bid orally at a dosage of 300 mg/m2 per dose.

[001366] In other embodiments, the VEGF antagonist is SU5416 and is administered intravenously biw at a dosage range of from about 50 mg/m2 to about 300 mg/m2, e. g. , from about 50 mg/m2 to about 75 mg/m2, from about 75 mg/m2 to about 100 mg/m2, from about 100 mg/m2 to about 125 mg/m2, from about 125 mg/m2 to about 150 mg/m2, from about 150 mg/m2 to about 175 mg/m2, from about 175 mg/m2 to about 200 mg/m2, from about 200 mg/m2 to about 250 mg/m2, or from about 250 mg/m2 to about 300 mg/m2. In a particular embodiment, SU5416 is administered i. v. biw at a dosage of 145 mg/m2.

[001367] In other embodiments, the VEGF antagonist is ZD6476 and is administered orally at a dosage of from about 50 mg per dose to about 500 mg per dose daily, e. g. , from about 50 mg/day to about 75 mg/day, from about 75 mg/day to about 100 mg/day, from about 100 mg/day to about 125 mg/day, from about 125 mg/day to about 150 mg/day, from about 150 mg/day to about 175 mg/day, from about 175 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day,-from about 300 mg/day to about 350 mg/day, from about 350 mg/day to about 400 mg/day, from about 400 mg/day to about 450 mg/day, or from about 450 mg/day to about 500 mg/day.

[001368] In other embodiments, the VEGF antagonist is bevacizumab (Avastiifrm) and is administered intravenously once every two weeks or once every three weeks at a dosage of from about 5 mg/kg-to about 25 mg/kg, e. g., from about 5 mg/kg to about 7.5 mg/kg, from about 7.5 mg/kg to about 10 mg/kg, from about 10 mg/kg to about 12.5 mg/kg, from about 12.5 mg/kg to about 15 mg/kg, from about 15 mg/kg to about 20 mg/kg, or from about 20 mg/kg to about 25 mg/kg.

[001369] In other embodiments, the VEGF antagonist is ZD4190 and is administered orally at a dosage of from about 5 mg/kg per day to about 200 mg/kg per day, e. g. , a daily dosage of from about 5 mg/kg to about 10 mg/kg, from about 10 mg/kg to about 15 mg/kg, from about 15 mg/kg to about 25 mg/kg, from about 25 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 75 mg/kg, from about 75 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 125 mg/kg, from about 125 mg/kg to about 150 mg/kg, from about 150 mg/kg to about 175 mg/kg, or from about 175 mg/kg to about 200 mg/kg.

[001370] In other embodiments, the VEGF antagonist is PTK787/ZK22584 and is administered orally at a daily dosage of from about 200 mg to about 2000 mg, e. g., from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 600 mg, from about 600 mg to about 700 mg, from about 700 mg to about 800 mg, from about 800 mg to about 900 mg, from about 900 mg to about 1000 mg, from about 1000 mg to about 1100 mg, from about 1100 mg to about 1200 mg, from about 1200 mg to about 1300 mg, from about 1300 mg to about 1400 mg, from about 1400 mg to about 1500 mg, from about 1500 mg to about 1600 mg, from about 1600 mg to about 1700 mg, from about 1700 mg to about 1800 mg, from about 1800 mg to about 1900 mg, or from about 1900 mg to about 2000 mg.

[001371] In other embodiments, the VEGF antagonist is Angiozyme and is administered subcutaneously at a daily dosage of from about 50 mg/m2 to about 500 mg/m2, e. g., from about 50 mg/m2 to about 75 mg/m2, from about 75 mg/m2 to about 100 mg/m2, from about 100 mg/m2 to about 125 mg/m2, from about 125 mg/m2 to about 150 mg/m2, from about 175 mg/m2 to about 200 mg/m2, from about 200 mg/m2 to about 225 mg/in2, from about 225 mg/m2 to about 250 mg/m2, from about 250 mg/m2 to about 300 mg/m2, from about 300 mg/m2 to about 350 mg/m2, from about 350 mg/m2 to about 400 mg/m2, from about 400 mg/m2 to about 450 mg/m2, or from about 450 mg/m2 to about 500 mg/m2.

[001372] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily detenninable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

Type I interferon receptor agonists [001373] A Type I interferon receptor agonist can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001374] In some embodiments, the Type I receptor agonist is an IFN-a. Effective dosages of an IFN-a can range from about 1 ug to about 30 µg, from about 3 llg to about 27 u. g, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 ig to about 180 ug, or from about 18 llg to about 90 µg.

[001375] Effective dosages of Infergen (g) consensus IFN-a include about 3 µg, about 9 ug, about 15 u, g, about 18 µg, or about 27 ug of drug per dose. Effective dosages of IFN-a2a and IFN- a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 pg to 180 µg, or about 135 u. g, of drug per dose.

Effective dosages of PEGylated IFN-a2b can contain an amount of about 0. 5 ug to 1. 5, ug of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 18 ug to about 90 tg, or from about 27 llg to about 60 µg, or about 45, ug, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001376] In some embodiments, a Type I interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen. The first dosing regimen of Type I interferon receptor agonist (also referred to as"the induction regimen") generally involves administration of a higher dosage of the Type I interferon receptor agonist. For example, in the case of InfergenX consensus IFN-a (CIFN), the first dosing regimen comprises administering CIFN at about 9 u, g, about 15 u. g, about 18 gag, or about 27 u. g. The first dosing regimen can encompass a single dosing event, or at least two or more dosing events. The first dosing regimen of the Type I interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001377] The first dosing regimen of the Type I interferon receptor agonist is administered for a first period of time, which time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.

[001378] The second dosing regimen of the Type I interferon receptor agonist (also referred to as "the maintenance dose") generally involves administration of a lower amount of the Type I interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CIFN at least about 3 gg, at least about 9 pg, at least about 15 u. g, or at least about 18 gag. The second dosing regimen can encompass a single dosing event, or at least two or more dosing events.

[001379] The second dosing regimen of the Type I interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

TNF antagonists [001380] Effective dosages of a TNF-a antagonist range from 0. 1 ug to 40 mg per dose, e. g., from about 0.1 llg to about 0.5 gag per dose, from about 0.5 llg to about 1. 0 ug per dose, from about 1.0 llg per dose to about 5. zug per dose, from about 5.0 wu to about 10 u. g per dose, from about 10 u. g to about 20 u. g per dose, from about 20 wu per dose to about 30 u. g per dose, from about 30 zg per dose to about 40 u. g per dose, from about 40 llg per dose to about 50 Rg per dose, from about 50 Rg per dose to about 60 ug per dose, from about 60 llg per dose to about 70 g per dose, from about 70 gag to about 80 ug per dose, from about 80 Rg per dose to about 100 llg per dose, from about 100 u. g to about 150 pg per dose, from about 150 ug to about 200 u. g per dose, from about 200 u, g per dose to about 250 ug per dose, from about 250 u. g to about 300 pg per dose, from about 300 ig to about 400 ug per dose, from about 400 u. g to about 500 ug per dose, from about 500 ug to about 600 u. g per dose, from about 600 u. g to about 700 llg per dose, from about 700 u. g to about 800 lug per dose, from about 800 ug to about 900 ug per dose, from about 900 u, g to about 1000 u. g per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001381] In some embodiments, the TNF-a antagonist is ENBREL etanercept. Effective dosages of etanercept range from about 0. 1 ug to about 40 mg per dose, from about 0. 1 u, g to about 1 wu per dose, from about 1 u, g to about 10 llg per dose, from about 10 gag to about 100 u, g per dose, from about 100 u, g to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001382] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[001383] In some embodiments, the TNF-a antagonist is REMICADE&commat;. Effective dosages of REMICADE range from about about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg-, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[001384] In some embodiments the TNF-a antagonist is HUMIRATM. Effective dosages of HUMIRATM range from about 0.1 Zg to about 35 mg, from about 0.1 llg to about 1 u. g, from about 1 Rg to about 10 u. g, from about 10 llg to about 100 u. g, from about 100 ug to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg,-from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[0013851 In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[001386] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001387] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

SAPK inhibitors [001388] Effective dosages of a SAPK inhibitor range from about 5 mg to about 3000 mg, e. g., from about 5 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 500 mg, from about 500 mg to about 1000 mg, from about 1000 mg to about 1500 mg, from about 1500 mg to about 2000 mg, from about 2000 mg to about 2500 mg, or from about 2500 mg to about 3000 mg.

[001389] In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

Effective dosages of pirfenidone or a specific pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos. , 5,310, 562; 5,518, 729; 5,716, 632; and 6,090, 822.

[001390] Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001391] Pirfenidone is typically administered orally. Pirfenidone can be administered orally daily in a single dose or in two or more divided doses.

[001392] In some embodiments, pirfenidone or a pirfenidone analog is administered throughout the entire course of Type II interferon receptor agonist/VEGF antagonist combination therapy.

In other embodiments, pirfenidone or a pirfenidone analog is administered less than the entire course of Type II interferon receptor agonist/VEGF antagonist combination therapy, e. g. , only during the first phase of Type II interferon receptor agonist/VEGF antagonist combination therapy, only during the second phase of Type II interferon receptor agonist/VEGF antagonist combination therapy, or some other portion of the Type II interferon receptor agonist/VEGF antagonist combination therapy treatment regimen.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat proliferative disorders [001393] In connection with each of the methods described herein, the invention provides embodiments in which a therapeutic agent is administered to the patient by a controlled drug delivery device. In some embodiments, a therapeutic agent is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver a therapeutic agent to the patient substantially continuously or continuously by subcutaneous infusion.

[001394] In other embodiments, a therapeutic agent is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the combination therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the combination therapy.

VEGF antagonists [001395] Effective dosages of a VEGF antagonist range from about 10 mg to about 1500 mg per dose, e. g. , from about 10 mg per dose to about 25 mg per dose, from about 25 mg per dose to about to about 50 mg per dose, from about 50 mg to about 75 mg per dose, from about 75 mg to about 100 mg per dose, from about 100 mg per dose to about 150 mg per dose, from about 150 mg per dose to about 200 mg per dose, from about 200 mg per dose to about 250 mg per dose, from about 250 mg per dose to about 300 mg per dose, from about 300 mg per dose to about 350 mg per dose, from about 350 mg per dose to about 400 mg per dose, from about 400 mg per dose to about 450 mg per dose, from about 450 mg per dose to about 500 mg per dose, from about 500 mg per dose to about 600 mg per dose, from about 600 mg per dose to about 700 mg per dose, from about 700 mg per dose to about 800 mg per dose, from about 800 mg per dose to about 900 mg per dose, from about 900 mg per dose to about 1000 mg per dose, from about 1000 mg per dose to about 1100 mg per dose, from about 1100 mg per dose to about 1200 mg per dose, from about 1200 mg per dose to about 1300 mg per dose, from about 1300 mg per dose to about 1400 mg per dose, or from about 1400 mg per dose to about 1500 mg per dose.

[001396] In some embodiments, effective dosages of a VEGF antagonist are expressed as mg per body surface area (mg/m2). In these embodiments, effective dosages of a VEGF antagonist are from about 10 mg/m2 to about 500 mg/m2, e. g. , from about 10 mg/m2 to about 25 mg/m2, from about 25 mg/m2 to about 50 mg/m2, from about 50 mg/m2 to about 75 mg/m2, from about 75 mg/m2 to about 100 mg/m2, from about 100 mg/m2 to about 125 mg/m2, from about 125 mg/m2 to about 150 mg/m2, from about 150 mg/m2 to about 175 mg/m2, from about 175 mg/m2 to about 200 mg/in2, from about 225 mg/m2, from about 225 mg/m2 to about 250 mg/m2, from about 250 mg/m2 to about 300 mg/m2, from about 300 mg/m2 to about 350 mg/m2, from about 350 mg/m2 to about 400 mg/m2, from about 400 mg/m2 to about 450 mg/m2, or from about 450 mg/m2 to about 500 mg/m2.

[001397] In some embodiments, effective dosages of a VEGF antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 5 mg/kg body weight to about 200 mg/kg body weight, e. g. , from about 5.0 mg/kg body weight to about 10 mg/kg body weight, from about 10 mg/kg body weight to about 15 mg/kg body weight, from about 15 mg/kg body weight to about 25 mg/kg body weight, from about 25 mg/kg body weight to about 50 mg/kg body weight, from about 50 mg/kg body weight to about 75 mg/kg body weight, from about 75 mg/kg body weight to about 100 mg/kg body weight, from about 100 mg/kg body weight to about 125 mg/kg body weight, from about 125 mg/kg body weight to about 150 mg/kg body weight, or from about 150 mg/kg body weight to about 200 mg/kg body weight.

[001398] Exemplary, non-limiting VEGF antagonists that are administered in a subject combination therapy are SU5416, SU6668, ZD4190, ZD6474, Avastin monoclonal antibody, ZM323881, PTK787/ZK22584,. and AngiozymeTM anti VEGFR ribozyme.

[001399] In many embodiments, a VEGF antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time (e. g. , 2 years, 3 years, or longer). The VEGF antagonist can be administered three times a day (tid), twice a day (bid), daily (qd), every other day (qod), twice per week (biw), three times per week (tiw), once per week (qw), every other week (qow), three times per month, once every 21 days, once monthly, substantially continuously, or continuously.

[001400] In some embodiments, the VEGF antagonist is SU 6668, and is administered orally twice daily (bid) at a dosage-of from about 50 mg/m2 to about 500 mg/m2, e. g. , from about 50 mg/m2 to about 75 mg/m2, from about 75 mg/m2 to about 100 mg/m2, from about 100 mg/m2 to about 125 mg/m2, from about 125 mg/m2 to about 150 mg/rn2, from about 150 mg/m2 to about 200 mg/m2, from about 200 mg/m2 to about 250 mg/m2, from about 250 mg/m2 to about 300 mg/m2, from about 300 mg/m2 to about 350 mg/m2, from about 350 mg/m2 to about 400 mg/m2, from about 400 mg/m2 to about 450 mg/m2, or from about 450 mg/m2 to about 500 mg/m2. In a particular embodiment, SU 6668 is administered bid orally at a dosage of 300 ing/m2 per dose.

[001401] In other embodiments, the VEGF antagonist is SU5416, and is administered intravenously biw at a dosage range of from about 50 mg/m2 to about 300 mg/m2, e. g., from about 50 mg/m2 to about 75 mg/in2, from about 75 mg/m2 to about 100 mg/m2, from about 100 mg/m2 to about 125 mg/m2, from about 125 mg/m2 to about 150 mg/m2, from about 150 mg/m2 to about 175 mg/m2, from about 175 mg/m2 to about 200 mg/m2, from about 200 mg/m2 to about 250 mg/m2, or from about 250 mg/m2 to about 300 mg/m2 In a particular embodiment, SU5416 is administered i. v. biw at a dosage of 145 mg/m2.

[001402] In other embodiments, the VEGF antagonist is ZD6476 and is administered orally at a dosage of from about-50 mg per dose to about 500 mg per dose daily, e. g. , from about 50 mg/day to about 75 mg/day, from about 75 mg/day to about 100 mg/day, from about 100 mg/day to about 125 mg/day, from about 125 mg/day to about 150 mg/day, from about 150 mg/day to about 175 mg/day, from about 175 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 350 mg/day to about 400 mg/day, from about 400 mg/day to about 450 mg/day, or from about 450 mg/day to about 500 mg/day.

[001403] In other embodiments, the VEGF antagonist is bevacizumab (AvastinTM) and is administered intravenously once every two weeks or once every three weeks at a dosage of from about 5 mg/kg to about 25 mg/kg, e. g. , from about 5 mg/kg to about 7.5 mg/kg, from about 7.5 mg/kg to about 10 mg/kg, from about 10 mg/kg to about 12.5 mg/kg, from about 12.5 mg/kg to about 15 mg/kg, from about 15 mg/kg to about 20 mg/kg, or from about 20 mg/kg to about 25 mg/kg.

[001404] In other embodiments, the VEGF antagonist is ZD4190 and is administered orally at a dosage of from about 5 mg/kg per day to about 200 mg/kg per day, e. g. , a daily dosage of from about 5 mg/kg to about 10 mg/kg, from about 10 mg/kg to about 15 mg/kg, from about 15 mg/kg to about 25 mg/kg, from about 25 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 75 mg/kg, from about 75 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 125 mg/kg, from about 125 mg/kg to about 150 mg/kg, from about 150 mg/kg to about 175 mg/kg, or from about 175 mg/kg to about 200 mg/kg.

[001405] In other embodiments, the VEGF antagonist is PTK787/ZK22584 and is administered orally at a daily dosage of from about 200 mg to about 2000 mg, e. g. , from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 600 mg, from about 600 mg to about 700 mg, from about 700 mg to about 800 mg, from about 800 mg to about 900 mg, from about 900 mg to about 1000 mg, from about 1000 mg to about 1100 mg, from about 1100 mg to about 1200 mg, from about 1200 mg to about 1300 mg, from about 1300 mg to about 1400 mg, from about 1400 mg to about 1500 mg, from about 1500 mg to about 1600 mg, from about 1600 mg to about 1700 mg, from about 1700 mg to about 1800 mg, from about 1800 mg to about 1900 mg, or from about 1900 mg to about 2000 mg.

[001406] In other embodiments, the VEGF antagonist is Angiozyme and is administered subcutaneously at a daily dosage of from about 50 mg/m2 to about 500 mg/m2, e. g. , from about 50 mg/m2 to about 75 mg/m2, from about 75 mg/m2 to about 100 mg/m2, from about 100 mg/m2 to about 125 mg/m2, from about 125 mg/m2 to about 150 mg/m2, from about 175 mg/m2 to about 200 mg/m2, from about 200 mg/m2 to about 225 mg/m2, from about 225 mg/m2 to about 250 mg/m2, from about 250 mg/m2 to about 300 mg/m2, from about 300 mg/m2 to about 350 mg/m2, from about 350 mg/m2 to about 400 mg/m2, from about 400 mg/m2 to about 450 mg/m2, or from about 450 mg/m2 to about 500 mg/m2.

[001407] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

TNF antagonists [001408] Effective dosages of a TNF-a antagonist range from 0.1 llg to 40 mg per dose, e. g., from about 0.1 llg to about 0.5 llg per dose, from about 0. 5 ug to about 1.0 u. g per dose, from about 1.0 llg per dose to about 5.0 wu per dose, from about 5.0 llg to about 10 llg per dose, from about 10 llg to about 20 ug per dose, from about 20 µg per dose to about 30 u. g per dose, from about 30 llg per dose to about 40 ttg per dose, from about 40 µg per dose to about 50 ug per dose, from about 50 ßg per dose to about 60 llg per dose, from about 60 gg per dose to about 70 u, g per dose, from about 70 µg to about 80 Fg per dose, from about 80 llg per dose to about 100 llg per dose, from about 100 sug to about 150 u. g per dose, from about 150 llg to about 200 gag per dose, from about 200 ßg per dose to about 250 Fg per dose, from about 250 llg to about 300 u. g per dose, from about 300 u. g to about 400 vug per dose, from about 400 u, g to about 500 u, g per dose, from about 500 ug to about 600 tug per dose, from about 600 ug to about 700 Zg per dose, from about 700 u, g to about 800 u. g per dose, from about 800 u. g to about 900 u. g per dose, from about 900 µg to about 1000 ug per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001409] In some embodiments, the TNF-a antagonist is ENBREL etanercept. Effective dosages of etanercept range from about 0. 1 u. g to about 40 mg per dose, from about 0.1 pg to about 1 µg per dose, from about 1 u. g to about 10 u. g per dose, from about 10 u. g to about 100 Rg per dose, from about 100 ug to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001410] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g. , from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[001411] In some embodiments, the TNF-a antagonist is REMICADEC. Effective dosages of REMICADE range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[001412] In some embodiments the TNF-a antagonist is HUMIRATM. Effective dosages of HUMIRATM range from about 0.1 p. g to about 35 mg, from about 0.1 ßg to about 1 u. g, from about 1 ug to about 10 tug, from about 10 llg to about 100 ag, from about 100 ug to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[001413] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[001414] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001415] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

SAPK inhibitors [001416] Effective dosages of a SAPK inhibitor range from about 5 mg to about 3000 mg, e. g., from about 5 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 500 mg, from about 500 mg to about 1000 mg, from about 1000 mg to about 1500 mg, from about 1500 mg to about 2000 mg, from about 2000 mg to about 2500 mg, or from about 2500 mg to about 3000 mg.

[001417] In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

Effective dosages of pirfenidone or a specific pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos. , 5,310, 562; 5,518, 729; 5,716, 632; and 6,090, 822.

[001418] Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001419] Pirfenidone is typically administered orally. Pirfenidone can be administered orally daily in a single dose or in two or more divided doses.

[001420] In some embodiments, pirfenidone or a pirfenidone analog is administered throughout the entire course of a subject combination therapy (e. g. , VEGF antagonist/TNF antagonist combination therapy, VEGF antagonist/SAPK inhibitor combination therapy, etc. ). In other embodiments, pirfenidone or a pirfenidone analog is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

Type ll interferon receptor agonists [001421] In some embodiments, the Type II interferon receptor agonist is an IFN-&gamma;. In some of these embodiments, the IFN-y is Actimmune human IFN-&gamma;1b.

[001422] Effective dosages of IFN-y can range from about 0.5 µg/m2 to about 500 µg/m2, usually from about 1.5 pg/m2 to 200 pg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 llg of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously.

[001423] In specific embodiments of interest, IFN-&gamma; is administered to an individual in a unit dosage form of from about 25 µg to about 500 u. g, from about 50 wu to about 400 u, g, or from about 100 jig to about 300 ug. In particular embodiments of interest, the dose is about 200 ug IFN-&gamma;. In many embodiments of interest, IFN-ylb is administered.

[001424] Where the dosage is 200 ug IFN-y per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 µg IFN-&gamma; per kg body weight to about 1. 48 ug IFN-y per kg body weight.

[001425] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-&gamma; dosage ranges from about 150, ug/m2 to about 20 ug/m2. For example, an IFN-&gamma; dosage ranges from about 20 µg/m2 to about 30 µg/m2, from about 30 µg/m2 to about 40 sug/m2, from about 40 µg/m2 to about 50 µg/m2, from about 50 µg/m2 to about 60, ug/m2, from about 60 µg/m2 to about 70 Fg/m2, from about 70 µg/m2 to about 80 µg/m2, from about 80 Fg/m2 to about 90 llg/m2, from about 90 pg/m2 to about 100 , ug/m2, from about 100 µg/m2 to about 110 µg/m2, from about 110 pg/m2 to about 120 µg/m2, from about 120 llg/m2 to about 130 ug/m2, from about 130 ug/m2 to about 140 µg/m2, or from about 140 µg/m2 to about 150 µg/m2. In some embodiments, the dosage groups range from about 25 ug/m2 to about 100 µg/m2. In other embodiments, the dosage groups range from about 25 µg/m2 to about 50 µg/m2.

[001426] In some embodiments, the IFN-y is Actimmune# human IFN-ylb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 gg, 50 µg, 100 µg, 150 µg, or 200 wog.

Type I interferon receptor agonists [001427] A Type I interferon receptor agonist can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001428] In some embodiments, the Type I receptor agonist is an IFN-a. Effective dosages of an IFN-a can range from about 1 ug to about 30 ug, from about 3 ug to about 27 ug, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 jig to about 180 ug, or from about 18 ug to about 90 ug.

[001429] Effective dosages of Infergen (g) consensus IFN-a include about 3 gg, about 9 ug, about 15 Rg, about 18 ug, or about 27 ug of drug per dose. Effective dosages of IFN-a2a and IFN- a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 ug to 180 u. g, or about 135 µg, of drug per dose.

Effective dosages of PEGylated IFN-a2b can contain an amount of about 0.5 llg to 1.5 llg of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 18 ug to about 90 ug, or from about 27 ug to about 60 ug, or about 45 , g, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001430] In some embodiments, a Type I interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen. The first dosing regimen of Type I interferon receptor agonist (also referred to as"the induction regimen") generally involves administration of a higher dosage of the Type I interferon receptor agonist. For example, in the case of Infergen RO consensus IFN-a (CIFN), the first dosing regimen comprises administering CIFN at about 9 lAg, about 15 ug, about 18 ug, or about 27 ug. The first dosing regimen can encompass a single dosing event, or at least two or more dosing events. The first dosing regimen of the Type I interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001431] The first dosing regimen of the Type I interferon receptor agonist is administered for a first period of time, which time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.

[001432] The second dosing regimen of the Type I interferon receptor agonist (also referred to as "the maintenance dose") generally involves administration of a lower amount of the Type I interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CIFN at least about 3 ug, at least about 9 ug, at least about 15 u. g, or at least about 18 u. g. The second dosing regimen can encompass a single dosing event, or at least two or more dosing events.

[001433] The second dosing regimen of the Type I interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

METHODS OF TREATMENT [001434] The present invention provides methods of treating proliferative disorders, including angiogenesis-mediated disorders, cancer, and fibrotic disorders. In some embodiments, the methods involve administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist, a stress-activated protein kinase (SAPK) inhibitor, and a third therapeutic agent. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a vascular endothelial growth factor (VEGF) antagonist. In other embodiments, the methods involve administering a VEGF antagonist and a SAPK inhibitor.

1) Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat proliferative disorders [001435] In some embodiments, a subject method for treating a proliferative disease comprises co-administration of a Type II interferon receptor agonist with a Type I interferon receptor agonist. In one embodiment, the disease therapy comprises IFN-alpha co-administered with IFN-gamma. The methods generally involve administering a therapeutically effective amount of the interferon receptor agonist combination to an individual in need thereof.

[001436] Individuals who are to be treated according to the methods of the invention include individuals who have been clinically diagnosed with a disease mediated by angiogenesis, cancer, or a fibrotic disorder.

[001437] In carrying out the methods of interferon therapy in an individual as described above, the Type I interferon receptor agonist and the Type II interferon receptor agonist are in some embodiments administered in the same formulation. In other embodiments, the Type I interferon receptor agonist and the Type II interferon receptor agonist are administered in separate formulations. When administered in separate formulations, the Type I interferon receptor agonist and the Type II interferon receptor agonist can be administered substantially simultaneously, or can be administered within about 24 hours of one another. In many embodiments, the Type I interferon receptor agonist and the Type II interferon receptor agonist are administered subcutaneously in multiple doses.

[001438] A Type II interferon receptor agonist can be administered daily, twice daily, every other day, twice a week, three times a week, or substantially continuously or continuously.

Effective dosages of a Type II interferon receptor agonist can range from about 1 pg to about 1000 µg.

[001439] In some embodiments, the Type II interferon receptor agonist is IFN-gamma. Effective dosages of IFN-gamma can range from about 25 u, g/dose to about 300 µg/dose, from about 10 µg/dose to about 100 u. g/dose, from about 100 µg/dose to about 300 llg/dose, from about 200 Fg/dose to about 300 u. g/dose, or from about 100 µg/dose to about 1000 Rg/dose.

[001440] A Type I interferon receptor agonist can be administered daily (qd), every other day (qod), twice a week (tiw), once a week (qw), three times a week (tiw), every other week (qow), three times per month, once monthly, substantially continuously or continuously.

[001441] In some embodiments, the Type I interferon receptor agonist is an IFN-alpha. Effective dosages of an IFN-alpha can range from about 1 ug to about 200 u, g, e. g. , from about 1 llg to about 30 u, g, from about 3 llg to about 27 µg, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 llg to about 180 ug, or from about 18 zug to about 90 u. g.

[001442] Effective dosages of InfergenW consensus IFN-alpha can contain an amount of about 3 u. g, about 6 wu, about 9 µg, about 12 ug, about 15 u. g, about 18 u. g, about 21 u. g, about 24 u. g, about 27 gg, or about 30 gag, of drug per dose. Effective dosages of IFN-a2a and IFN-a2b can contain an amount of about 3 million Units (MU) to about 30 MU of drug per dose. Effective dosages of PEGASYSOPEGylated IFN-a2a can contain an amount of about 5 µg to about 500 u. g, or about 45 zig to about 450 u. g, or about 60 µg to about 400 u. g, or about 75 llg to about 350 µg, or about 90 llg to about 300 wog, about 105 gag to about 270 u. g, or about 120 Zg to about 240 µg, or about 135 llg to about 210 u. g, or about 150 µg to about 180 µg, or about 135 gg, of drug per dose. Effective dosages of PEG-INTRON (g) PEGylated IFN-a2b can contain an amount of about 0. 5 u. g to about 5.0 ug, or about. 75 ig to about 3. 5 gag, or about 1. zug to about 3. 0 µg, or about 1.25 u. g to about 2. 5 u. g, or about 1.5 µg to about 2.0 u. g, of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 9 µg to about 200 u. g, or about 12 µg to about 180 µg, or about 15 u. g to about 150 u. g, or about 18 wu to about 120 u. g, or about 21 wu to about 90 u. g, or about 24 ug to about 75 u. g, or about 27 u. g to about 60 u. g, or about 45 µg, of CIFN amino acid weight per dose of PEG-CIFN. Effective dosages of monoPEG (30 kD, linear) -ylated CIFN can contain an amount of about 5 u. g to about 500 u, g, or about or about 45 llg to about 450 µg, or about 60 ßg to about 400 u. g, or about 75 u. g to about 350 u, g, or about 90 llg to about 300 u. g, about 105 ug to about 270 ug, or about 120 u. g to about 240 u. g, or about 135 llg to about 210 u, g, or about 150 llg to about 180 u. g, or about 135, ug, of drug per dose.

[001443] In many embodiments, the Type I interferon receptor agonist and/or the Type II interferon receptor agonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. Dosage regimens can include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or monthly administrations.

[001444] In some embodiments, the invention provides any of the above-described methods in which the desired dosage of IFN-a is administered subcutaneously to the patient by bolus delivery qd, qod, tiw, biw, qw, qow, three times per month, or monthly, or is administered subcutaneously to the patient per day by substantially continuous or continuous delivery, for the desired treatment duration. In other embodiments, the invention provides any of the above- described methods in which the desired dosage of PEGylated IFN-alpha (PEG-IFN-alpha) is administered subcutaneously to the patient by bolus delivery qw, qow, three times per month, or monthly for the desired treatment duration.

[001445] In some embodiments, the invention provides methods using a synergistically effective amount of a Type I interferon receptor agonist and a Type II interferon receptor agonist in the treatment of a patient. In some embodiments, the invention provides methods using a synergistically effective amount of an IFN-alpha and IFN-gamma in the treatment of a patient.

In one embodiment, the invention provides a method using a synergistically effective amount of a consensus IFN-alpha and IFN-gamma in the treatment of a patient.

[001446] In general, a synergistically effective amount of a consensus interferon (CIFN) and IFN-gamma suitable for use in the methods of the invention is provided by a dosage ratio of 1 llg CIFN: 10 u. g IFN-gamma, where both CIFN and IFN-gamma are unPEGylated and unglycosylated species.

[001447] In one embodiment, the invention provides a method using a synergistically effective amount of INFERGEN&commat;consensus IFN-alpha and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of INFERGEN containing an amount of about 1 llg to about 30 Rg, of drug per dose of INFERGEN (g), suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-gamma containing an amount of about 10 wog to about 300 Zg of drug per dose of IFN-gamma, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired treatment duration.

[001448] In another embodiment, the invention provides a method using a synergistically effective amount of INFERGENt) consensus IFN-alpha and IFN-gamma in the treatment of a patient comprising administering to the patient. a dosage of INFERGEN (g) containing an amount of about 1 ig to about 9 u. g, of drug per dose of INFERGENO, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 10 u. g to about 100 ig of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per. day substantially continuously-or continuously, for the desired treatment duration.

[001449] In another embodiment, the invention provides a method using a synergistically effective amount of (S) consensus IFN-alpha and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of INFERGENO containing an amount of about 1 fig of drug per dose of INFERGENt), subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-gamma containing an amount of about 10 Fg to about 50 llg of drug per dose of IFN-gamma, subcutaneously qd, qod, tiw, biw, qw, qow,. three times per month, once monthly, or per day substantially continuously or continuously, for the desired treatment duration.

[001450] In another embodiment, the invention provides a method using a synergistically effective amount of (R) consensus IFN-alpha and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of INFERGENO containing an amount of about 9 wu of drug per dose of INFERGEN, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-gamma containing an amount of about 90 Fg to about 100 u, g of drug per dose of IFN-gamma, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired treatment duration.

[001451] In another embodiment, the invention provides a method using a synergistically effective amount of (S) consensus IFN-alpha and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of INFERGENS containing an amount of about 30 ug of drug per dose of INFERGEN&commat;, suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-gamma containing an amount of about 200 llg to about 300 u. g of drug per dose of IFN-gamma, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired treatment duration.

[001452] In another embodiment, the invention provides a method using a synergistically effective amount of PEGylated consensus IFN-alpha and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of PEGylated consensus IFN-alpha (PEG-CIFN) containing an amount of about 4 ig to about 60 u. g ofCIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-gamma containing an amount of about 30 u, g to about 1,000 Zg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, for the desired treatment duration.

[001453] In another embodiment, the invention provides a method using a synergistically effective amount of PEGylated consensus IFN-alpha and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of PEGylated consensus IFN-alpha (PEG-CIFN) containing an amount of about 18 tug to about 24 llg of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-gamma containing an amount of about 100 zig to about 300 tug of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, for the desired treatment duration.

[001454] In general, a synergistically effective amount of IFN-alpha 2a or 2b or 2c and IFN- gamma suitable for use in the methods of the invention is provided by a dosage ratio of 1 million Units (MU) IFN-alpha 2a or 2b or 2c: 30 llg IFN-gamma, where both IFN-alpha 2a or 2b or 2c and IFN-gamma are unPEGylated and unglycosylated species.

[001455] In another embodiment, the invention provides a method using a synergistically effective amount of IFN-alpha 2a or 2b or 2c and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of IFN-alpha 2a containing an amount of about 1 MU to about 20 MU of drug per dose of IFN-alpha 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-gamma containing an amount of about 30 llg to about 600 wu of drug per dose of IFN-gamma, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired treatment duration.

[001456] In another embodiment, the invention provides a method using a synergistically effective amount of IFN-alpha 2a or 2b or 2c and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of IFN-a2a containing an amount of about 3 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-gamma. containing an amount of about 100 pg of drug per dose of IFN-gamma, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired treatment duration.

[001457] In another embodiment, the invention provides a method using a synergistically effective amount of IFN-alpha 2a or 2b or 2c and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of IFN-alpha 2a containing an amount of about 10 MU of drug per dose of IFN-alpha 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN- gamma containing an amount of about 300 Uug of drug per dose of IFN-gamma, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired treatment duration.

[001458] In another embodiment, the invention provides a method using a synergistically effective amount of PEGylated IFN-alpha 2a and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of PEGASYS containing an amount of about 90 llg to about 360 ; j, g, of drug per dose of PEGASYS (t, suboutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- gamma containing an amount of about 30 p. g to about 1,000 ng, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired treatment duration.

[001459] In another embodiment, the invention provides a method using a synergistically effective amount of PEGASYSOPEGylated IFN-alpha 2a and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of PEGASYS (» containing an amount of about 180 u. g of drug per dose of PEGASYSOO, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-gamma containing an amount of about 100 jig to about 300 p. g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired treatment duration.

[001460] In another embodiment, the invention provides a method using a synergistically effective amount of PEG-INTRON (g) PEGylated IFN-alpha 2b and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage of PEG-INTRON (g) containing an amount of about 0.75 llg to about 3.0 vag of drug per kilogram of body weight per dose of PEG- INTRONO, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-containing an amount of about 30 ug to about 1, 000, ug of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired treatment duration.

[001461] In another embodiment, the invention provides a method using a synergistically effective amount of PEG-INTRON (g) PEGylated IFN-alpha 2b and IFN-gamma in the treatment of a patient comprising administering to the patient a dosage ofPEG-INTRON (R) containing an amount of about 1.5 ig of drug per kilogram of body weight per dose of PEG-INTRON (g), subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 100 Uug to about 300 u. g of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired treatment duration. la. Type II interferon receptor agonist, Type I interferon receptor agonist and pirfenidone in combination therapy to treat proliferative disorders [001462] In one aspect, the present invention provides combination therapy for the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, comprising administering effective amounts of pirfenidone (or a pirfenidone analog), a Type I interferon receptor agonist and a Type II interferon receptor agonist. In some embodiments, the method employs a Type I interferon receptor agonist that is IFN-alpha. In other embodiments, the method employs a Type II interferon receptor agonist that is IFN-gamma. In still other embodiments, the method employs a Type I interferon receptor agonist that is IFN- alpha and a Type II interferon receptor agonist that is IFN-gamma.

[001463] IFN-a and IFN-y are typically administered subcutaneously. For example, IFN-a and IFN-y can be administered subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for a period of from about 2 weeks to about 52 weeks, from about 52 weeks to about 2 years, or longer.

[001464] In one embodiment, the invention provides a method using an effective amount of INFERGEN (» consensus IFN-a, IFN-, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of INFERGEN (g) containing an amount of about 1 llg to about 30 gg of drug per dose of INFERGENX), subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, and a dosage of IFN-y containing an amount of about 10 ug to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 50 mg to about 5,000 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001465] In another embodiment, the invention provides a method using an effective amount of INFERGEN (g) consensus IFN-a, IFN-y, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of INFERGENtE containing an amount of about 3 u, g to about 30 llg of drug per dose of INFERGEN, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, and a dosage of IFN-y containing an amount of about 30 ug to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 300 mg to about 3,000 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001466] In another embodiment, the invention provides a method using an effective amount of INFERGEN (X3consensus IFN-a, IFN-y, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disease, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of INFERGEN (g containing an amount of about 1 wu to about 9 jig of drug per dose of INFERGEN (D, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, and a dosage of IFN-y containing an amount of about 10 Zg to about 100 llg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 100 mg to about 1,000 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001467] In another embodiment, the invention provides a method using an effective amount of INFERGEN (» consensus IFN-a, IFN-y, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of INFERGENO containing an amount of about 9 llg of drug per dose of INFERGENO, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, and a dosage of IFN-y containing an amount of about 90 llg to about 100 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 500 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001468] In another embodiment, the invention provides a method using an effective amount of INFERGENt) consensus IFN-a, IFN-y, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disorder, including any fibrotic disease, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of INFERGEN (g) containing an amount of about 30 u. g of drug per dose of INFERGEN (g), suboutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, and a dosage of IFN-y containing an amount of about 200 ug to about 300 llg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 1, 000 mg to about 2,000 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001469] In another embodiment, the invention provides a method using an effective amount of a consensus IFN-a, IFN-y, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG- CIFN) containing an amount of about 10 ug to about 150 wg of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, and a total weekly dosage of IFN-gamma containing an amount of about 100 u. g to about 1,500 u, g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 50 mg to about 5,000 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001470] In another embodiment, the invention provides a method using an effective amount of a consensus IFN-a, IFN-y, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of about 5 pg to about 500 u. g, or about 45 Zg to about 450 p. g, or about 60 gg to about 400 ug, or about 75 ag to about 350 g, or abut 90 Zg to about 300 ug, about 105 ug to about 270 ug, or about 120 llg to about 240 ug, or about 135 ug to about 210 jig, or about 150 ug to about 180 ag, or about 135 ug, of drug per dose, subcutaneously qw, qow, three times per month, or monthly, and a total weekly dosage of IFN- gamma containing an amount of about 100 llg to about 1, 500 ug of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 50 mg to about 5,000 mg of drug orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001471] In another embodiment, the invention provides a method using an effective amount of INFERGEN (g) consensus IFN-a, IFN-y, and pirfenidone or a specific pirfenidone analog in the / treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of INFERGEN containing an amount of about 5 llg to about 150 ag of drug per dose of INFERGEN#, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, and a dosage of IFN-y containing an amount of about 10 µg to about 300 00 tg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 1,000 mg to about 10,000 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001472] In another embodiment, the invention provides a method using an effective amount of INFERGEN (tconsensus IFN-a, IFN-, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of INFERGENS containing an amount of about 5 Fg to about 45 jig of drug per dose of INFERGENO, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, and a dosage of IFN-y containing an amount of about 50 llg to about 300 p, g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 1,000 mg to about 3,000 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration.

[001473] In another embodiment, the invention provides a method using an effective amount of INFERGEN#consensus IFN-&alpha;, IFN-&gamma;, and pirfenidone or a specific pirfenidone analog in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of INFERGEN (g) containing an amount of about 45 llg of drug per dose of INFERGEN (g), suboutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, and a dosage of IFN-y containing an amount of about 100 llg to about 300 ßg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, in combination with a dosage of pirfenidone or a specific pirfenidone analog containing an amount of about 1,000 mg to about 2,000 mg of drug per dose orally qd, optionally in two or more divided doses per day, for the desired treatment duration. lb. Further combinations comprising a Type II interferon receptor agonist and a Type I interferon receptor agonist in combination therapy to treat proliferative disorders [001474] Any of the above-described treatment regimens for treating a fibrotic disorder can be modified to include administering an effective amount of N-acetylcysteine (NAC).

[001475] Effective dosages of NAC can range from about 100 mg to about 1000 mg per day, or from about 100 mg to about 500 mg per day, or from about 500 mg to about 750 mg per day, or from about 750 mg to about 1000 mg per day, or from about 400 mg to about 3600 mg per day, or from about 800 mg to about 2400 mg per day, or from about 1000 mg to about 1800 mg per day, or from about 1200 mg to about 1600 mg per day.

[001476] NAC can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, three times per day, or in divided daily doses ranging from 2 to 5 times daily.

[001477] NAC can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001478] In some embodiments, NAC is administered throughout the entire course of the subject combination therapy. In other embodiments, NAC is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[001479] In some embodiments, NAC is administered at a dosage of NAC containing an amount of from about 500 mg to about 3000 mg of NAC per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration.

[001480] In some embodiments, NAC is administered at a dosage of 500 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001481] In other embodiments, NAC is administered at a dosage of 600 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001482] In other embodiments, NAC is administered at a dosage of 750 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

In other embodiments, NAC is administered at a dosage of 1000 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration. lc. Type I interferon receptor agonist and Type II interferon receptor agonist combination therapy as an adjuvant to cancer therapy [001483] In some embodiments, the present invention provides methods for combination therapy using a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog), where the interferon receptor agonists (with or without pirfenidone/pirfenidone analog) are administered as adjuvant therapy to a primary cancer therapy. Primary cancer therapies include surgery (e. g. , surgical removal of cancerous tissue), radiation therapy, bone marrow transplantation, chemotherapeutic treatment, biological response modifier treatment, and certain combinations of the foregoing.

[001484] Radiation therapy includes, but is not limited to, x-rays or gamma rays that are delivered from either an externally applied source such as a beam, or by implantation of small radioactive sources.

[001485] Chemotherapeutic agents are non-peptidic (i. e. , non-proteinaceous) compounds that reduce proliferation of cancer cells, and encompass cytotoxic agents and cytostatic agents.

Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant (vinca) alkaloids, and steroid hormones.

[001486] Agents that act to reduce cellular proliferation are known in the art and widely used.

Such agents include alkylating agents, such as nitrogen mustard, nitrosoureas, ethylenimine derivatives, allcyl sulfonates, and triazenes, including, but not limited to, mechlorethamine, cyclophosphamide (CytoxanTM), melphalan (L-sarcolysin), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, dacarbazine, and temozolomide.

[001487] Antimetabolite agents include folic acid analogs, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, including, but not limited to, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine, 6-mercaptopurine (6-MP), pentostatin, 5-fluorouracil (5-FU), methotrexate, 10-propargyl-5, 8-dideazafolate (PDDF, CB3717), 5, 8-dideazatetrahydrofolic acid (DDATHF), leucovorin, fludarabine phosphate, pentostatine, and gemcitabine.

[001488] Suitable natural products and their derivatives, (e. g. , vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), include, but are not limited to, Ara-C, paclitaxel (Taxol (»), docetaxel (Taxotere (g)), deoxycoformycin, mitomycin-C, L- asparaginase, azathioprine; brequinar; alkaloids, e. g. vincristine, vinblastine, vinorelbine, vindesine, etc. ; podophyllotoxins, e. g. etoposide, teniposide, etc. ; antibiotics, e. g. anthracycline, daunorubicin hydrochloride (daunomycin, rubidomycin, cerubidine), idarubicin, doxorubicin, epirubicin and morpholino derivatives, etc. ; phenoxizone biscyclopeptides, e. g. dactinomycin; basic glycopeptides, e. g. bleomycin; anthraquinone glycosides, e. g. plicamycin (mithramycin) ; anthracenediones, e. g. mitoxantrone ; azirinopyrrolo indolediones, e. g. mitomycin; macrocyclic immunosuppressants, e. g. cyclosporine, FK-506 (tacrolimus, prograf), rapamycin, etc. ; and the like.

[001489] Other anti-proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[001490] Microtubule affecting agents that have antiproliferative activity are also suitable for use and include, but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e. g. , NSC 33410), dolstatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol), TaxolOO derivatives, docetaxel (Taxotere (g)), thiocolchicine (NSC 361792), trityl cysterin, vinblastine sulfate, vincristine sulfate, natural and synthetic epothilones including but not limited to, eopthilone A, epothilone B, discodermolide ; estramustine, nocodazole, and the like.

[001491] Hormone modulators and steroids (including synthetic analogs) that are suitable for use include, but are not limited to, adrenocorticosteroids, e. g. prednisone, dexamethasone, etc. ; estrogens and pregestins, e. g. hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estradiol, clomiphene, tamoxifen; etc. ; and adrenocortical suppressants, e. g. aminoglutethimide; 17a-ethinylestradiol ; diethylstilbestrol, testosterone, fluoxymesterone, dromostanolone propionate, testolactone, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, Flutamide (Drogenil), Toremifene (Fareston), and Zoladexg. Estrogens stimulate proliferation and differentiation, therefore compounds that bind to the estrogen receptor are used to block this activity. Corticosteroids may inhibit T cell proliferation.

[001492] Other chemotherapeutic agents include metal complexes, e. g. cisplatin (cis-DDP), carboplatin, etc. ; ureas, e. g. hydroxyurea; and hydrazines, e. g. N-methylhydrazine; epidophyllotoxin; a topoisomerase inhibitor; procarbazine; mitoxantrone ; leucovorin; tegafur; etc.. Other anti-proliferative agents of interest include immunosuppressants, e. g. mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); Ressac (ZD 1839, 4- (3-chloro-4-fluorophenylamino)-7-methoxy-6- (3- (4-morpholinyl) propoxy) quinazoline); etc.

[001493]"Taxanes"include paclitaxel, as well as any active taxane derivative or pro-drug.

"Paclitaxel" (which should be understood herein to include analogues, formulations, and derivatives such as, for example, docetaxel, TAXOLTM, TAXOTERETM (a formulation of docetaxel), 10-desacetyl analogs of paclitaxel and 3'N-desbenzoyl-3'N-t-butoxycarbonyl analogs of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see also WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076; U. S. Pat. Nos. 5,294, 637; 5,283, 253; 5,279, 949; 5,274, 137; 5,202, 448; 5,200, 534; 5,229, 529; and EP 590,267), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co. , St. Louis, Mo. (T7402 from Taxus brevifolia ; or T-1912 from Taxus yannanensis).

[001494] Paclitaxel should be understood to refer to not only the common chemically available form of paclitaxel, but analogs and derivatives (e. g., Taxotere Tm docetaxel, as noted above) and paclitaxel conjugates (e. g. , paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylose).

[001495] Also included within the term"taxane"are a variety of known derivatives, including both hydrophilic derivatives, and hydrophobic derivatives. Taxane derivatives include, but not limited to, galactose and mannose derivatives described in International Patent Application No.

WO 99/18113; piperazino and other derivatives described in WO 99/14209; taxane derivatives described in WO 99/09021, WO 98/22451, and U. S. Patent No. 5,869, 680; 6-thio derivatives described in WO 98/28288 ; sulfenamide derivatives described in U. S. Patent No. 5,821, 263; and taxol derivative described in U. S. Patent No. 5,415, 869. It further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98/58927 ; WO 98/13059; and U. S. Patent No. 5,824, 701.

[001496] Biological response modifiers suitable for use in connection with the methods of the invention include, but are not limited to, (1) inhibitors of tyrosine kinase (RTK) activity; (2) inhibitors of serine/threonine kinase activity; (3) tumor-associated antigen antagonists, such as antibodies that bind specifically to a tumor antigen; (4) apoptosis receptor agonists; (5) interleukin-2; (6) IFN-a ; (7) IFN-y (8) colony-stimulating factors ; and (9) inhibitors of angiogenesis.

[0014971 In one aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor, such as type I receptor tyrosine kinase inhibitors (e. g., inhibitors of epidermal growth factor receptors), type II receptor tyrosine kinase inhibitors (e. g., inhibitors of insulin receptor), type III receptor tyrosine kinase inhibitors (e. g. , inhibitors of platelet-derived growth factor receptor), and type IV receptor tyrosine kinase inhibitors (e. g. , fibroblast growth factor receptor). In other embodiments, the tyrosine kinase inhibitor is a non-receptor tyrosine kinase inhibitor, such as inhibitors of src kinases or janus kinases.

[001498] In another aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an inhibitor of a receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is genistein. In other embodiments, the inhibitor is an EGFR tyrosine kinase-specific antagonist, such as IRESSATM gefitinib (ZD18398 ; Novartis), TARCEVATM erolotinib (OSI-774; Roche; Genentech; OSI Pharmaceuticals), or tyrphostin AG1478 (4- (3-chloroanilino)-6, 7-dimethoxyquinazoline. In still other embodiments, the inhibitor is any indolinone antagonist of Flk-l/KDR (VEGF-R2) tyrosine kinase activity described in U. S. Patent Application Publication No. 2002/0183364 Al, such as the indolinone antagonists of Flk-l/KDR (VEGF-R2) tyrosine kinase activity disclosed in Table 1 on pages 4- 5 thereof. In further embodiments, the inhibitor is any of the substituted 3- [ (4, 5, 6, 7-tetrahydro- 1H-indol-2-yl) methylene]-1, 3-dihydroindol-2-one antagonists of Flk-l/KDR (VEGF-R2), FGF-Rl or PDGF-R tyrosine kinase activity disclosed in Sun, L. , et al. , J. Med. Chem., 43 14 : 2655-2663 (2000). In additional embodiments, the inhibitor is any substituted 3- [ (3- or 4- carboxyethylpyrrol-2-yl) methylidenyl] indolin-2-one antagonist of Flt-1 (VEGF-Rl), Flk- 1/KDR (VEGF-R2), FGF-Rl or PDGF-R tyrosine kinase activity disclosed in Sun, L. , et al., J.

Med. Chem. , 42 (25) : 5120-5130 (1999).

[001499] In another aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an inhibitor of a non-receptor tyrosine kinase involved in growth factor signaling pathway (s).

In some embodiments, the inhibitor is an antagonist of JAK2 tyrosine kinase activity, such as tyrphostin AG490 (2-cyano-3- (3, 4-dihydroxyphenyl)-N- (benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of bcr-abl tyrosine kinase activity, such as GLEEVECTM imatinib mesylate (STI-571 ; Novartis).

[001500] In another aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is a serine/threonine kinase inhibitor. hi some embodiments, the serine/threonine kinase inhibitor is a receptor serine/threonine kinase inhibitor, such as antagonists of TGF-ß receptor serine/threonine kinase activity. In other embodiments, the serine/threonine kinase inhibitor is a non-receptor serine/threonine kinase inhibitor, such as antagonists of the serine/threonine kinase activity of the MAP kinases, protein kinase C (PKC), protein kinase A (PKA), or the cyclin-dependent kinases (CDKs).

[001501] In another aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an inhibitor of one or more kinases involved in cell cycle regulation. In some embodiments, the inhibitor is an antagonist of CDK2 activation, such as tryphostin AG490 (2-cyano-3- (3, 4- dihydroxyphenyl)-N- (benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of CDKl/cyclin B activity, such as alsterpaullone. In still other embodiments, the inhibitor is an antagonist of CDK2 kinase activity, such as indirubin-3'-monoxime. In additional embodiments, the inhibitor is an ATP pool antagonist, such as lometrexol (described in U. S. Patent Application Publication No. 2002/0156023 A1).

[001502] In another aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is a tumor-associated antigen antagonist, such as an antibody antagonist. In some embodiments involving the treatment of HER2-expressing tumors, the tumor-associated antigen antagonist is an anti-HER2 monoclonal antibody, such as HERCEPTINTM trastuzumab. In some embodiments involving the treatment of CD20-expressing tumors, such as B-cell lymphomas, the tumor-associated antigen antagonist is an anti-CD20 monoclonal antibody, such as RITUXANTM rituximab.

[001503] In another aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is a tumor growth factor antagonist. In some embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor (EGF), such as an anti-EGF monoclonal antibody. In other embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor receptor erbBl (EGFR), such as an anti-EGFR monoclonal antibody inhibitor of EGFR activation or signal transduction, e. g. ERBITUXTM cetuximab.

[001504] In another aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an Apo-2 ligand agonist. In some embodiments, the Apo-2 ligand agonist is any of the Apo-2 ligand polypeptides described in WO 97/25428.

[001505] In another aspect, the invention contemplates the combination of a Type II interferon receptor agonist and a Type I interferon receptor agonist (with or without pirfenidone/pirfenidone analog) as an adjuvant to any therapy in which the cancer patient receives treatment with at least one additional antineoplastic drug, where the additional drug is an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent is a vascular endothelial cell growth factor (VEGF) antagonist, such as an anti-VEGF monoclonal antibody, e. g. AVASTINTM bevacizumab (Genentech). In other embodiments, the anti-angiogenic agent is an antagonist of VEGF-Rl, such as an anti-VEGF-Rl monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of VEGF-R2, such as an anti-VEGF- R2 monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of basic fibroblast growth factor (bFGF), such as an anti-bFGF monoclonal antibody. In other embodiments, the anti-angiogenic factor is an antagonist of bFGF receptor, such as an anti- bFGF receptor monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of TGF-P, such as an anti-TGF-P monoclonal antibody. In other embodiments, the anti-angiogenic agent is an antagonist of TGF- (3 receptor, such as an anti-TGF- (3 receptor monoclonal antibody. In other embodiments, the anti-angiogenic agent is a retinoic acid receptor (RXR) ligand, such as any RXR ligand described in U. S. Patent Application Publication No. 2001/0036955 Al or in any of U. S. Pat. Nos. 5, 824, 685; 5, 780, 676; 5,399, 586; 5,466, 861; 4,810, 804 ; 5,770, 378; 5,770, 383; or 5,770, 382. In still other embodiments, the , anti-angiogenic agent is a peroxisome proliferator-activated receptor (PPAR) gamma ligand, such as any PPAR gamma ligand described in U. S. Patent Application Publication No.

2001/0036955 Al. ld. Type II interferon receptor agonist and Type I interferon receptor agonist in combination therapy to treat proliferative disorders, further comprising administering a side effect management agent [001506] The methods of the invention provide for the co-administration of an effective amount of an additional agent that reduces the severity or occurrence of side effects frequently experienced by individuals as a result of treatment with Type I interferon receptor agonist and/or Type II interferon receptor agonist. Side effects include, but are not limited to, fever, malaise, tachycardia, chills, headache, arthralgia, myalgia, myelosuppression, suicide ideation, platelet suppression, neutropenia, lymphocytopenia, erythrocytopenia (anemia), and anorexia.

[001507] Agents suitable for use in connection with the methods of the present invention include analgesics, antiinflammatories, antipsychotics, antineurotics, anxiolytics, and hematopoietic agents. In addition, the invention contemplates the use of any agent for palliative care of patients suffering from pain in the course of treatment with the interferon receptor agonist combination therapy in accordance with the present methods. It will be understood that any such agent can be administered using an amount, dosing frequency and duration of treatment that would be known to the clinician in order to accomplish the reduction or avoidance of side effects caused by the interferon receptor agonist combination therapies used in the methods of the invention. In many cases, instructions for the appropriate use of such agents are provided in the package insert of the commercially available pharmaceutical product.

2) Type II interferon receptor agonist, SAPK inhibitor, and third therapeutic agent in combination therapy for treating proliferative disorders [001508] In one aspect, the present invention provides combination therapy for the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, comprising administering an effective amount of a Type II interferon receptor agonist, an effective amount of a SAPK inhibitor, and at least a third therapeutic agent. In some embodiments, the method employs a Type II interferon receptor agonist that is IFN-gamma. In some embodiments, the method employs SAPK inhibitor that is pirfenidone or a pirfenidone analog. In some embodiments, the third therapeutic agent is one or more of a non-steroidal anti-inflammatory drug, a histamine type 2 receptor antagonist, an antacid, and a hematopoietic agent.

09] In one aspect, the invention provides a method of treating fibrosis in a patient comprising administering to the patient an amount of a Type II interferon receptor agonist and a SAPK inhibitor effective to reduce fibrosis or reduce the rate of progression of fibrotic disease, and further comprising administering a third therapeutic agent.

10] In another aspect, the invention provides a method of increasing function in an organ affected by fibrosis in a patient, comprising administering to the patient an amount of a Type II interferon receptor agonist and a SAPK inhibitor effective to increase function of the affected organ, and further comprising administering a third therapeutic agent in an amount effective to reduce a side effect (s) of a Type II interferon receptor agonist and/or a SAPK inhibitor.

11] In another aspect, the invention provides a method of reducing the incidence of a complication of cirrhosis of the liver in a patient suffering from liver fibrosis, comprising administering to the patient an amount of a Type II interferon receptor agonist and a SAPK inhibitor effective to reduce the incidence of a complication of cirrhosis of the liver, and further comprising administering a third therapeutic agent in an amount effective to reduce a side effect (s) of a Type II interferon receptor agonist and/or a SAPK inhibitor.

12] Effective dosages of IFN-y can range from about 0.5 pg/m2 to about 500 Lg/in2, usually from about 1. 5, ug/m2 to 200, ug/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 llg of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously.

13] In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 Fg to about 500 gg, from about 50 u, g to about 400 u. g, or from about 100 u. g to about 300 u. g. In particular embodiments of interest, the dose is about 200 llg IFN-&gamma;. In many embodiments of interest, IFN-&gamma;1b is administered.

14] Where the dosage is 200 u. g IFN-y per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4. 4, ug IFN-y per kg body weight to about 1. 48 llg IFN-per kg body weight.

15] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 ig/m to about 20 llg/m2. For example, an IFN-y dosage ranges from about 20 llg/m2 to about 30 gg/m2, from about 30, ug/m2 to about 40 Fg/m2, from about 40 Fg/m2 to about 50 µg/m2, from about 50 llg/m2 to about 60 µg/m2, from about 60, ug/m2 to about 70 µg/m2, from about 70 µg/m2 to about 80, ug/m2, from about 80 Fg/m2 to about 90 ug/m, from about 90 llg/m2 to about 100 µg/m2, from about 100 pLg/m2 to about 110 Zg/m2, from about 110 µg/m2 to about 120 µg/m2, from about 120 llg/m2 to about 130 µg/m2, from about 130 µg/m2 to about 140 ug/m2, or from about 140, ug/m2 to about 150 µg/m2. In some embodiments, the dosage groups range from about 25 µg/m2 to about 100 µg/m2. In other embodiments, the dosage groups range from about 25 ug/m2 to about 50 Fg/m2.

[001516] IFN-y is typically administered subcutaneously. For example, IFN-y can be administered subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for a period of from about 2 weeks to about 52 weeks, from about 52 weeks to about 2 years, or longer.

[001517] Pirfenidone is typically administered orally. Pirfenidone can be administered orally daily in a single dose or in two or more divided doses.

[001518] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos., 5, 310, 562; 5,518, 729; 5,716, 632; and 6,090, 822.

[001519] In one embodiment, the invention provides a method using an effective amount of IFN- , pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising co-administering to the patient a dosage of IFN-y containing an amount of about 10 µg to about 3 00 gag of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent, for the desired treatment duration.

[001520] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 llg to about 300 ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously ; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001521] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 ttg to about 300 00 tg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001522] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 gag to about 300 jig of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 1200 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001523] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 0 llg to about 300 ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 800 mg to about 2400 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001524] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 u. g to about 300 lug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 400 mg to about 1200 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001525] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 0 llg to about 100 00, ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001526] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 u, g to about 100 00, ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 1200 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001527] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 ig to about 100 ig of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 800 mg to about 2400 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001528] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 gg Rg to about l 00 llg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 400 mg to about 1200 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001529] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 200 u. g to about 300 llg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001530] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 200 llg to about 300 ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 1200 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001531] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 200 Rg to about 300 llg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 800 mg to about 2400 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001532] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 200 u. g to about 300 ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 400 mg to about 1200 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001533] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a total weekly dosage of IFN- gamma containing an amount of about 100 ig to about 1,500 llg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range-of from about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001534] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a total weekly dosage of IFN- gamma containing an amount of about 100 u. g to about 1, 500, ug of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 1200 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001535] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a total weekly dosage of IFN- gamma containing an amount of about 100 zig to about 1,500 u. g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 800 mg to about 2400 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001536] In another embodiment, the invention provides a method using an effective amount of IFN-y, pirfenidone or a specific pirfenidone analog, and a third therapeutic agent in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient comprising administering to the patient a total weekly dosage of IFN- gamma containing an amount of about 100 ag to about 1,500 Rg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously; a fixed dosage of pirfenidone or a pirfenidone analog in the range of from about 400 mg to about 1200 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a third therapeutic agent for the desired treatment duration.

[001537] In any of the above-described regimens, a third therapeutic agent is selected from a NSAID (e. g. , ibuprofen, acetaminophen); a histamine type 2 receptor antagonist; a hematopoietic agent; and an antacid.

[001538] Any of the above-described treatment regimens for treating a fibrotic disorder can be modified to include administering an effective amount of N-acetylcysteine (NAC).

[001539] Effective dosages of NAC can range from about 100 mg to about 1000 mg per day, or from about 100 mg to about 500 mg per day, or from about 500 mg to about 750 mg per day, or from about 750 mg to about 1000 mg per day, or from about 400 mg to about 3600 mg per day, or from about 800 mg to about 2400 mg per day, or from about 1000 mg to about 1800 mg per day, or from about 1200 mg to about 1600 mg per day.

[001540] NAC can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, three times per day, or in divided daily doses ranging from 2 to 5 times daily.

[001541] NAC can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001542] In some embodiments, NAC is administered throughout the entire course of the subject combination therapy. In other embodiments, NAC is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[001543] In some embodiments, NAC is administered at a dosage of NAC containing an amount of from about 500 mg to about 3000 mg of NAC per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration.

[001544] In some embodiments, NAC is administered at a dosage of 500 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001545] In other embodiments, NAC is administered at a dosage of 600 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001546] In other embodiments, NAC is administered at a dosage of 750 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001547] In other embodiments, NAC is administered at a dosage of 1000 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

3) Type II interferon receptor agonist and VEGF antagonist in combination therapy to treat proliferative disorders [001548] The instant invention provides combination therapies involving administering a Type II interferon receptor agonist and a VEGF antagonist in combined effective amounts for the treatment of proliferative disorders. In some embodiments, a subject combination therapy comprises administering a Type II interferon receptor agonist, a VEGF antagonist, and a Type I interferon receptor agonist in combined effective amounts for the treatment of proliferative disorders. In some embodiments, a subject combination therapy comprises administering a Type II interferon receptor agonist, a VEGF antagonist, and a TNF antagonist in combined effective amounts for the treatment of proliferative disorders. In some embodiments, a subject combination therapy comprises administering a Type II interferon receptor agonist, a VEGF antagonist, and a SAPK inhibitor in combined effective amounts for the treatment of proliferative disorders. In some embodiments, a subject combination therapy comprises administering a Type II interferon receptor agonist, a VEGF antagonist, a Type I interferon receptor agonist, and a TNF antagonist in combined effective amounts for the treatment of proliferative disorders. In some embodiments, a subject combination therapy comprises administering a Type II interferon receptor agonist, a VEGF antagonist, a Type I interferon receptor agonist, and a SAPK inhibitor in combined effective amounts for the treatment of proliferative disorders. In some embodiments, a subject combination therapy comprises administering a Type II interferon receptor agonist, a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts for the treatment of proliferative disorders.

[001549] In particular embodiments, the invention provides a method using an effective amount of IFN-y and a VEGF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of IFN-y containing an amount of from about 10 llg to about 300 lug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration.

[001550] In a particular embodiment, the invention provides a method using an effective amount of IFN-y and a VEGF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of IFN-y containing an amount of from about 10 wu to about 300 jig of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and a dosage of SU5416 containing an amount of 145 mg/m2 intravenously twice weekly for the desired treatment duration.

[001551] In a particular embodiment, the invention provides a method using an effective amount of IFN-y and a VEGF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of IFN-y containing an amount of from about 10 gag to about 300 ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and a dosage of SU6668 containing an amount of 300 mg/m2 orally twice daily for the desired treatment duration.

[001552] In a particular embodiment, the invention provides a method using an effective amount of IFN-y and a VEGF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of IFN-y containing an amount of from about 10 u. g to about 3 00 jig of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and a dosage of ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily for the desired treatment duration.

[001553] In a particular embodiment, the invention provides a method using an effective amount of IFN-y and a VEGF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of IFN-y containing an amount of from about 10 u. g to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and a dosage of ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily for the desired treatment duration.

[001554] In a particular embodiment, the invention provides a method using an effective amount of IFN-y and a VEGF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of IFN-y containing an amount of from about 10 u. g to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and a dosage of bevacizumab (Avastinj containing an amount of 5 mg/kg, 7.5 mg/kg, 10 mg/kg, or 15 mg/kg intravenously once every two weeks or once every three weeks for the desired treatment duration.

[001555] In a particular embodiment, the invention provides a method using an effective amount of IFN-y and a VEGF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of IFN-y containing an amount of from about 10 u, g to about 300 u, g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and a dosage of PTK787/ZK22584 containing an amount of 1500 mg/day orally for the desired treatment duration.

[001556] In a particular embodiment, the invention provides a method using an effective amount of IFN-and a VEGF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of IFN-y containing an amount of from about 10 llg to about 300 u, g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and a dosage of AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously.

[001557] Any of the above-described treatment regimens can be modified such that the IFN-y is Actimmune human IFN-Y I b, and is administered subcutaneously tiw in a dosage containing an amount of about 25 u. g, 50 u. g, 100 u. g, 150 u. g, or 200 pg.

3a. Type II interferon receptor agonist and VEGF antagonist in combination therapy, further comprising administering a Type I interferon receptor agonist, to treat proliferative disorders [001558] Any of the above combination therapies can be modified to include administration of a Type I interferon receptor agonist. In many embodiments, the Type I interferon receptor agonist is IFN-a.

[001559] In some embodiments, the invention provides a method using an effective amount of INFERGENtconsensus IFN-a, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of INFERGENS containing an amount of about 1 llg to about 30 ug of drug per dose of INFERGEN&commat; subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously for the desired treatment duration.

[001560] In some embodiments, the invention provides a method using an effective amount of INFERGEN (E consensus IFN-a, IFN-and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of INFERGEN containing an amount of about 9 g to about 15 u. g of drug per dose of INFERGENX suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously for the desired treatment duration.

[001561] In some embodiments, the invention provides a method using an effective amount of PEGylated consensus IFN-a, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens ; and a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 tig to about 100 llg of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

[001562] In some embodiments, the invention provides a method using an effective amount of PEGylated consensus IFN-a, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 40 llg to about 80, ug of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

[001563] In some embodiments, the invention provides a method using an effective amount of PEGylated IFN-&alpha; 2a or 2b or 2c, IFN-y and a VEGF antagonist in the treatment of a- proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of a IFN-&alpha; 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously for the desired treatment duration.

[001564] In some embodiments, the invention provides a method using an effective amount of PEGASYSOPEGylated IFN-a2a, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of PEGASYS containing an amount of about 90 llg to about 360 u, g, or about 180 80, ug, of drug per dose of PEGASYSS subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

[001565] In some embodiments, the invention provides a method using an effective amount of PEG-INTRO #PEGylated IFN-a2b, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of PEG-INTRON# containing an amount of about 0.75 llg to about 3.0 ug, or about 1. 0 llg to about 1. 5 ug, of drug per kilogram of body weight per dose of PEG-INTRON (g) subcutaneously biw, qw, qow, three times per month, or monthly for the desired treatment duration.

[001566] In some embodiments, the invention provides a method using an effective amount of monoPEG (30 kD, linear) -ylated consensus IFN-a, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about l 00 pLg to about 200 ug, or about l 50 Uug, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, once every 8 days, once every 10 days, qow, three times per month, or once monthly for the desired treatment duration.

3b. Type II interferon receptor agonist and VEGF antagonist in combination therapy, further comprising administering a TNF antagonist, to treat proliferative disorders [001567] Any of the above combination therapies can be modified to include administration of a TNF-a antagonist. hi many embodiments, the TNF antagonist is selected from the group consisting of ENBREL, REMICADE and HUMIRATM.

[001568] In some embodiments, the invention provides a method using an effective amount of a TNF antagonist, IFN-y, and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

3c. Type II interferon receptor agonist and VEGF antagonist in combination therapy, further comprising administering pirfenidone or a pirfenidone analog, to treat proliferative disorders [001569] Any of the above combination therapies can be modified to include administration of pirfenidone or a pirfenidone analog in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally.

[001570] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 5 mg/kg body weight to about 125 mg/kg body weight administered orally qd for the desired treatment duration.

[001571] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 400 mg to about 3600 mg administered orally qd for the desired treatment duration.

[001572] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 400 mg to about 2400 mg administered orally qd for the desired treatment duration.

[001573] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 800 mg to about 2400 mg administered orally qd for the desired treatment duration.

[001574] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 800 mg administered orally qd for the desired treatment duration.

[001575] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 1000 mg to about 1800 mg administered orally qd for the desired treatment duration.

[001576] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 1200 mg to about 3600 mg administered orally qd for the desired treatment duration.

[001577] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 1200 mg to about 1600 mg administered orally qd for the desired treatment duration.

[001578] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 1200 mg administered orally qd for the desired treatment duration.

[001579] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog, IFN-y and a VEGF antagonist in the treatment of a proliferative disorder in a patient, comprising administering to the patient a dosage of IFN-y and a dosage of a VEGF antagonist as in any of the above-described regimens; and a dosage of pirfenidone or a pirfenidone analog containing an amount of about 1800 mg to about 3600 mg administered orally qd for the desired treatment duration.

3d. Type II interferon receptor agonist and VEGF antagonist in combination therapy, as an adjuvant to cancer therapy, to treat proliferative disorders [001580] In some embodiments, the present invention provides methods for combination therapy using a Type II interferon receptor agonist (e. g., IFN-y) and a VEGF antagonist, where the IFN-and the VEGF antagonist are administered as adjuvant therapy to a standard cancer therapy. Standard cancer therapies include surgery (e. g. , surgical removal of cancerous tissue), radiation therapy, bone marrow transplantation, chemotherapeutic treatment, biological response modifier treatment, and certain combinations of the foregoing.

[001581] Radiation therapy includes, but is not limited to, x-rays or gamma rays that are delivered from either an externally applied source such as a beam, or by implantation of small radioactive sources.

[001582] Chemotherapeutic agents are non-peptidic (i. e. , non-proteinaceous) compounds that reduce proliferation of cancer cells, and encompass cytotoxic agents and cytostatic agents.

Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant (vinca) alkaloids, and steroid hormones.

[001583] Agents that act to reduce cellular proliferation are known in the art and widely used.

Such agents include alkylating agents, such as nitrogen mustard, nitrosoureas, ethylenimine derivatives, alkyl sulfonates, and triazenes, including, but not limited to, mechlorethamine, cyclophosphamide (CytoxanTM), melphalan (L-sarcolysin), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, dacarbazine, and temozolomide.

[001584] Antimetabolite agents include folic acid analogs, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, including, but not limited to, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine, 6-mercaptopurine (6-MP), pentostatin, 5-fluorouracil (5-FU), methotrexate, 10-propargyl-5, 8-dideazafolate (PDDF, CB3717), 5, 8-dideazatetrahydrofolic acid (DDATHF), leucovorin, fludarabine phosphate, pentostatine, and gemcitabine.

[001585] Suitable natural products and their derivatives, (e. g. , vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), include, but are not limited to, Ara-C, paclitaxel (Taxol (g)), docetaxel (Taxotere (»), deoxycoformycin, mitomycin-C, L- asparaginase, azathioprine; brequinar; alkaloids, e. g. vincristine, vinblastine, vinorelbine, vindesine, etc. ; podophyllotoxins, e. g. etoposide, teniposide, etc. ; antibiotics, e. g. anthracycline, daunorubicin hydrochloride (daunomycin, rubidomycin, cerubidine), idarubicin, doxorubicin, epirubicin and morpholino derivatives, etc. ; phenoxizone biscyclopeptides, e. g. dactinomycin; basic glycopeptides, e. g. bleomycin; anthraquinone glycosides, e. g. plicamycin (mithramycin) ; anthracenediones, e. g. mitoxantrone; azirinopyrrolo indolediones, e. g. mitomycin; macrocyclic immunosuppressants, e. g. cyclosporine, FK-506 (tacrolimus, prograf), rapamycin, etc. ; and the like.

[001586] Other anti-proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[001587] Microtubule affecting agents that have antiproliferative activity are also suitable for use and include, but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e. g. , NSC 33410), dolstatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol), Taxol derivatives, docetaxel (Taxotere (g)), thiocolchicine (NSC 361792), trityl cysterin, vinblastine sulfate, vincristine sulfate, natural and synthetic epothilones including but not limited to, eopthilone A, epothilone B, discodermolide; estramustine, nocodazole, and the like.

[001588] Hormone modulators and steroids (including synthetic analogs) that are suitable for use include, but are not limited to, adrenocorticosteroids, e. g. prednisone, dexamethasone, etc. ; estrogens and pregestins, e. g. hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estradiol, clomiphene, tamoxifen; etc. ; and adrenocortical suppressants, e. g. aminoglutethimide; 17a-ethinylestradiol ; diethylstilbestrol, testosterone, fluoxymesterone, dromostanolone propionate, testolactone, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, Flutamide (Drogenil), Toremifene (Fareston), and Zoladexg. Estrogens stimulate proliferation and differentiation, therefore compounds that bind to the estrogen receptor are used to block this activity. Corticosteroids may inhibit T cell proliferation.

[001589] Other chemotherapeutic agents include metal complexes, e. g. cisplatin (cis-DDP), carboplatin, etc. ; ureas, e. g. hydroxyurea; and hydrazines, e. g. N-methylhydrazine; epidophyllotoxin; a topoisomerase inhibitor; procarbazine; mitoxantrone ; leucovorin ; tegafur; etc.. Other anti-proliferative agents of interest include immunosuppressants, e. g. mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); Iressa (ZD 1839, 4- (3-chloro-4-fluorophenylamino)-7-methoxy-6- (3- (4-morpholinyl) propoxy) quinazoline); etc.

[001590]"Taxanes"include paclitaxel, as well as any active taxane derivative or pro-drug.

"Paclitaxel" (which should be understood herein to include analogues, formulations, and derivatives such as, for example, docetaxel, TAXOLTM, TAXOTERETM (a formulation of docetaxel), 10-desacetyl analogs of paclitaxel and 3'N-desbenzoyl-3'N-t-butoxycarbonyl analogs of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see also WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076; U. S. Pat. Nos. 5,294, 637; 5,283, 253; 5,279, 949; 5,274, 137; 5,202, 448; 5,200, 534; 5,229, 529; and EP 590,267), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co. , St. Louis, Mo. (T7402 from Taxus brevifolia ; or T-1912 from Taxusyannanensis).

[001591] Paclitaxel should be understood to refer to not only the common chemically available form of paclitaxel, but analogs and derivatives (e. g., Taxotere docetaxel, as noted above) and paclitaxel conjugates (e. g. , paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylose).

[001592] Also included within the term"taxane"are a variety of known derivatives, including both hydrophilic derivatives, and hydrophobic derivatives. Taxane derivatives include, but not limited to, galactose and mannose derivatives described in International Patent Application No.

WO 99/18113; piperazino and other derivatives described in WO 99/14209 ; taxane derivatives described in WO 99/09021, WO 98/22451, and U. S. Patent No. 5,869, 680; 6-thio derivatives described in WO 98/28288 ; sulfenamide derivatives described in U. S. Patent No. 5,821, 263; and taxol derivative described in U. S. Patent No. 5,415, 869. It further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98/58927; WO 98/13059; and U. S. Patent No. 5,824, 701.

[001593] Biological response modifiers suitable for-use in connection with the methods of the invention include, but are not limited to, (1) inhibitors of tyrosine kinase (RTK) activity; (2) inhibitors of serine/threonine kinase activity; (3) tumor-associated antigen antagonists, such as antibodies that bind specifically to a tumor antigen ; (4) apoptosis receptor agonists; (5) interleukin-2; (6) IFN-a ; (7) IFN-y (8) colony-stimulating factors; and (9) inhibitors of angiogenesis.

[001594] In one aspect, the invention contemplates IFN-y and VEGF antagonist combination therapy as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a tyrosine kinase inhibitor. hi some embodiments, the tyrosine kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor, such as type I receptor tyrosine kinase inhibitors (e. g. , inhibitors of epidermal growth factor receptors), type II receptor tyrosine kinase inhibitors (e. g. , inhibitors of insulin receptor), type III receptor tyrosine kinase inhibitors (e. g., inhibitors of platelet-derived growth factor receptor), and type IV receptor tyrosine kinase inhibitors (e. g. , fibroblast growth factor receptor). In other embodiments, the tyrosine kinase inhibitor is a non-receptor tyrosine kinase inhibitor, such as inhibitors of src kinases or janus kinases.

[001595] In another aspect, the invention contemplates IFN-y and VEGF antagonist combination therapy as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of a receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is genistein. In other embodiments, the inhibitor is an EGFR tyrosine kinase-specific antagonist, such as IRESSATM gefitinib (ZD18398; Novartis), TARCEVATM erolotinib (OSI- 774; Roche; Genentech; OSI Pharmaceuticals), or tyrphostin AG1478 (4- (3-chloroanilino)-6, 7- dimethoxyquinazoline. In still other embodiments, the inhibitor is any indolinone antagonist of Flk-1/KDR (VEGF-R2) tyrosine kinase activity described in U. S. Patent Application Publication No. 2002/0183364 Al, such as the indolinone antagonists of Flk-1/KDR (VEGF- R2) tyrosine kinase activity disclosed in Table 1 on pages 4-5 thereof. In further embodiments, the inhibitor is any of the substituted 3- [ (4, 5,6, 7-tetrahydro-lH-indol-2-yl) methylene]-l, 3- dihydroindol-2-one antagonists of Flk-1/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity disclosed in Sun, L. , et al. , J. Med. Chem., 43 14 : 2655-2663 (2000). In additional embodiments, the inhibitor is any substituted 3- [ (3- or 4-carboxyethylpyrrol-2-yl) methylidenyl] indolin-2-one antagonist of Flt-1 (VEGF-Rl), Flk-I/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity disclosed in Sun, L. , et al. , J. Med. Chem. , 42 (25) : 5120- 5130 (1999).

[001596] In another aspect, the invention contemplates IFN-y and VEGF antagonist combination therapy as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of a non-receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is an antagonist of JAK2 tyrosine kinase activity, such as tyrphostin AG490 (2-cyano- 3- (3, 4-diliydroxyphenyl)-N- (benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of bcr-abl tyrosine kinase activity, such as GLEEVECTMimatinib mesylate (STI- 571; Novartis).

[001597] In another aspect, the invention contemplates IFN-y and VEGF antagonist combination therapy as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a serine/threonine kinase inhibitor. In some embodiments, the serine/threonine kinase inhibitor is a receptor serine/threonine kinase inhibitor, such as antagonists of TGF- [3 receptor serine/threonine kinase activity. In other embodiments, the serine/threonine kinase inhibitor is a non-receptor serine/threonine kinase inhibitor, such as antagonists of the serine/threonine kinase activity of the MAP kinases, protein kinase C (PKC), protein kinase A (PKA), or the cyclin-dependent kinases (CDKs).

[001598] In another aspect, the invention contemplates IFN-y and VEGF antagonist combination therapy as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of one or more kinases involved in cell cycle regulation. In some embodiments, the inhibitor is an antagonist of CDK2 activation, such as tryphostin AG490 (2-cyano-3- (3, 4-dihydroxyphenyl)-N- (benzyl)- 2-propenamide). In other embodiments, the inhibitor is an antagonist of CDKl/cyclin B activity, such as alsterpaullone. In still other embodiments, the inhibitor is an antagonist of CDK2 kinase activity, such as indirubin-3'-monoxime. In additional embodiments, the inhibitor is an ATP pool antagonist, such as lometrexol (described in U. S. Patent Application Publication No. 2002/0156023 A1).

[001599] In another aspect, the invention contemplates IFN-y and VEGF antagonist combination therapy as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an a tumor-associated antigen antagonist, such as an antibody antagonist. In some embodiments involving the treatment of HER2-expressing tumors, the tumor-associated antigen antagonist is an anti-HER2 monoclonal antibody, such as HERCEPTINTM trastuzumab. In some embodiments involving the treatment of CD20-expressing tumors, such as B-cell lymphomas, the tumor-associated antigen antagonist is an anti-CD20 monoclonal antibody, such as RITUXANTM rituximab.

[001600] In another aspect, the invention contemplates IFN-y and VEGF antagonist combination therapy as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a tumor growth factor antagonist. In some embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor (EGF), such as an anti-EGF monoclonal antibody. In other embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor receptor erbB 1 (EGFR), such as an anti-EGFR monoclonal antibody inhibitor of EGFR activation or signal transduction.

[001601] In another aspect, the invention contemplates IFN-y and VEGF antagonist combination therapy as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an Apo-2 ligand agonist. In some embodiments, the Apo-2 ligand agonist is any of the Apo-2 ligand polypeptides described in WO 97/25428.

[001602] Exemplary non-limiting examples of combination therapies that include treatment with radiation and a combination of a Type II interferon receptor agonist and a VEGF antagonist; or treatment with an additional chemotherapeutic agent and a combination of a Type II interferon receptor agonist and a VEGF antagonist, are as follows: [001603] 1) a dosage of IFN-y containing an amount of from about 10 ag to about 300 llg ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; and cisplatin in a dosage range of from about 5 mg/m2 to about 150 mg/m2 ; [001604] 2) a dosage of IFN-y containing an amount of from about 10 lAg to about 300 llg ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; and carboplatin in a dosage range of from about 5 mg/m2 to about 1000 mg/m2 ; [001605] 3) a dosage of IFN-y containing an amount of from about 10 ug to about 300 llg ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; and radiation in a dosage range of from about 200 cGy to about 8000 cGy; [001606] 4) a dosage of IFN-y containing an amount of from about 10 ug to about 300 lug ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; and paclitaxel in a dosage range of from about 40 mg/m2 to about 250 mg/m2 ; [001607] 5) a dosage of IFN-y containing an amount of from about 10 p, g to about 300 ig ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; and carboplatin in a dosage range of from about 5 mg/m2 to about 1000 mg/m2 ; [001608] 6) a dosage of IFN-y containing an amount of from about 10 Rg to about 300 pLg ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; and leucovorin in a dosage range of from about 5 mg/m2 to about 1000 mg/m2 ; [001609] 7) a dosage of IFN-&gamma; containing an amount of from about 10 llg to about 300 llg ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; and trastuzumab in an initial loading dose of 4 mg/kg and a weekly maintenance dose of 2 mg/kg; [001610] 8) a dosage of IFN-Y containing an amount of from about 10 ig to about 300 zg ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; trastuzumab in an initial loading dose of 4 mg/kg and a weekly maintenance dose of 2 mg/kg; and paclitaxel in a dosage range of from about 40 mg/m2 to about 250 mg/m2 ; [001611] 9) a dosage of IFN-&gamma; containing an amount of from about 10 llg to about 300 p. g ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; paclitaxel in a dosage range of from about 40 mg/m2 to about 250 mg/m2 ; and estramustine phosphate (Emoyte)) in a dosage range of from about 5 mg/m2 to about 1000 mg/m2 ; [001612] 10) a dosage of IFN-y containing an amount of from about 10 llg to about 300 u. g ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; and 5FU in a dosage range of from about 5 mg/m2 to about 5000 mg/m2 ; [001613] 11) a dosage of IFN-&gamma; containing an amount of from about 10 ug to about 300 00 Lg ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; 5FU in a dosage range of from about 5 mg/m2 to about 5000 mg/m2 ; and radiation in a dose of from about 200 cGy to about 8000 cGy ; [001614] 12) a dosage of IFN-y containing an amount of from about 10 u. g to about 300 u. g ; a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about-500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, where the VEGF antagonist is selected from a VEGF receptor tyrosine kinase inhibitor, an antibody to VEGF, an antibody to a VEGFR, and an anti-VEGF receptor ribozyme, a soluble VEGFR, an anti-VEGFR antisense, and an siRNA that inhibits a VEGFR; 5FU in a dosage range of from about 5 mg/m2 to about 5000 mg/m2 ; and paclitaxel in a dosage range of from about 40 mg/m2 to about 250 mg/m2.

3e. Type II interferon receptor agonist and VEGF antagonist in combination therapy, further comprising administering a side effect management agent, to treat proliferative disorders [001615] Any of the above combination therapies can be modified to include administration of a side effect management agent. For example, any of the above-described combination therapies can be modified to include administration of acetaminophen, ibuprofen, or other NSAID, an H2 blocker, or an antacid.

4) VEGF antagonist in combination with a TNF antagonist or a SAPK inhibitor to treat proliferative disorders [001616] The instant invention provides combination therapies involving administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, in combined effective amounts for the treatment of proliferative disorders. In some embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

[001617] In some embodiments, a subject combination therapy for the treatment of a proliferative disorder involves administering a VEGF antagonist, a TNF antagonist, and a SAPK inhibitor in combined effective amounts to treat the proliferative disorder. In some of these embodiments, the method further comprises administering an effective amount of a Type II interferon receptor agonist, e. g., IFN-Y. In some embodiments, the method further comprises administering an effective amount of a Type I interferon receptor agonist, e. g., IFN-a. In some embodiments, the method further comprises administering both a Type I interferon receptor agonist and a Type II interferon receptor agonist.

4a. VEGF antagonist in combination with a TNF antagonist to treat proliferative disorders [001618] The invention provides combination therapy for the treatment of proliferative disorders, comprising administering a VEGF antagonist and a TNF antagonist in combined effective amounts to treat the proliferative disorder. In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; and a dosage of a TNF antagonist containing an amount of from about 0.1 Zg to about 40 mg per dose, or from about 0.1 mg/kg to about 10 mg/kg per dose subcutaneously, intravenously, or orally qd, qod, tiw, or biw, or per day for the desired treatment duration.

[001619] In a particular embodiment, the invention provides a method using an effective amount of a VEGF antagonist and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of SU5416 containing an amount of 145 mg/m intravenously twice weekly for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (S in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001620] In a particular embodiment, the invention provides a method using an effective amount of a VEGF antagonist and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of SU6668 containing an amount of 300 mg/m2 orally twice daily for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (g) in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

21] In a particular embodiment, the invention provides a method using an effective amount of a VEGF antagonist and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

22] In a particular embodiment, the invention provides a method using an effective amount of a VEGF antagonist and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

23] In a particular embodiment, the invention provides a method using an effective amount of a VEGF antagonist and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of bevacizumab (Avastin) containing an amount of 5 mg/kg, 7.5 mg/kg, 10 mg/kg, or 15 mg/kg intravenously once every two weeks or once every three weeks for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEW in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001624] In a particular embodiment, the invention provides a method using an effective amount of a VEGF antagonist and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of PTK787/ZK22584 containing an amount of 1500 mg/day orally for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (g) in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001625] In a particular embodiment, the invention provides a method using an effective amount of a VEGF antagonist and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of Angiozymew containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

4b. VEGF antagonist, a TNF antagonist, and a Type II interferon receptor agonist in combination therapy to treat proliferative disorders [001626] Any of the above combination therapies using a VEGF antagonist and a TNF antagonist can be modified to include administration of a Type II interferon receptor agonist.

In many embodiments, the Type II interferon receptor agonist is IFN-Y. In certain embodiments, the IFN-y is Actimmune human IFN-ylb.

[001627] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and IFN-&gamma; in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 u. g to about 300 wog of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001628] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of SU5416 containing an amount of 145 mg/m2 intravenously twice weekly for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 llg to about 300 ig of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001629] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and IFN-in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of SU6668 containing an amount of 300 mg/m2 orally twice daily for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 g to about 300 gag of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001630] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 ig to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001631] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily for the desired treatment duration; a dosage of a TNF- a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEO in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 llg to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001632] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of bevacizumab (Avastin) containing an amount of 5 mg/kg, 7.5 mg/kg, 10 mg/kg, or 15 mg/kg intravenously once every two weeks or once every three weeks for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 llg to about 300 llg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001633] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of PTK787/ZK22584 containing an amount of 1500 mg/day orally for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 u, g to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001634] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 ug to about 300 u, g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001635] Any of the above-described treatment regimens can be modified such that the IFN-y is Actimmune human IFN-y Ib, and is administered subcutaneously tiw in a dosage containing an amount of about 25 ug, 50 ug, 100 u. g, 150 u, g, or 200 u. g.

4c. VEGF antagonist, a TNF antagonist, and a Type I interferon receptor agonist in combination therapy to treat proliferative disorders [001636] Any of the above VEGF antagonist/TNF antagonist combination therapies can be modified to include administration of a Type I interferon receptor agonist. In many embodiments, the Type I interferon receptor agonist is IFN-a.

[001637] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and INFERGEN (g) consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADES in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of INFERGENS containing an amount of about 1 vug to about 30 ug of drug per dose of INFERGENO subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously for the desired treatment duration.

[001638] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and INFERGEN O consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens ; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEO in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of INFERGENS containing an amount of about 9 u. g to about 15 llg of drug per dose of INFERGENO subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously for the desired treatment duration.

[001639] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and PEGylated consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELS in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (D in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 llg to about 100 . g of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

[001640] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and PEGylated consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEO in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 40 Fg to about 80 u, g of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

[001641] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and PEGylated IFN-a 2a or 2b or 2c in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of a IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously for the desired treatment duration.

[001642] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and PEGASYS (» PEGylated IFN-a2a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of PEGASYS containing an amount of about 90 ug to about 360 ; j. g, or about 180 u-g, of drug per dose of PEGASYS (C) suboutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

[001643] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and PEG-INTRON (g) PEGylated IFN-a2b in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (D in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of PEG-INTRO containing an amount of about 0. 75 gag to about 3. 0, ug, or about 1.0 llg to about 1.5 gg, of drug per kilogram of body weight per dose of PEG-INTRON subcutaneously biw, qw, qow, three times per month, or monthly for the desired treatment duration.

[001644] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a TNF antagonist, and monoPEG (30 kD, linear) -ylated consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEt) in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 u. g to about 200 u. g, or about 150 u, g, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

4d. VEGF antagonist, a TNF antagonist, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combination therapy to treat proliferative disorders [001645] Any of the above VEGF antagonist/TNF antagonist combination therapies can be modified to include administration of a Type I interferon receptor agonist and a Type II interferon agonist. In many embodiments, the Type I interferon receptor agonist is IFN-a. In many embodiments, the Type II interferon receptor agonist is IFN-y.

[001646] Thus, in particular embodiments, the invention provides a combination therapy for the treatment of proliferative disorders, comprising administering a VEGF antagonist, a TNF antagonist, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts for the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient (a) a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration; (b) a dosage of a TNF antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration ; (c) a dosage of IFN-y containing an amount of from about 10 llg to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and (d) a dosage of an IFN-a selected from the group consisting of (i) INFERGEN containing an amount of about 1 gag to about 30 u. g of drug per dose of INFERGEN (g) subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 llg to about 100 Rg of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day (iv) PEGASYSO containing an amount of about 90 llg to about 360 wu, or about 180 lug, of drug per dose of PEGASYS subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 gag to about 3. 0, ug, or about 1.0 llg to about 1.5 u. g, of drug per kilogram of body weight per dose of PEG-INTRONQD subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 u. g to about 200 u, g, or about 150 gg, of drug per dose of mono PEG (30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration.

4e. VEGF antagonist and SAPK inhibitor in combination therapy to treat proliferative disorders [001647] The invention provides combination therapy for the treatment of proliferative disorders, comprising administering a VEGF antagonist and a SAPK inhibitor in combined effective amounts to treat the proliferative disorder. In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; and a dosage of a SAPK inhibitor containing an amount of from about 0.1 llg to about 3600 mg per dose, or from about 0.1 mg/kg to about 10 mg/kg per dose subcutaneously, intravenously, or orally qd, qod, tiw, or biw, or per day for the desired treatment duration.

[001648] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; and a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration.

[001649] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; and a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, administered orally qd for the desired treatment duration.

[001650] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; and a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration.

[001651] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, administered orally qd for the desired treatment duration; and a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (Avastin : rm) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration.

[001652] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration.

[001653] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 800 mg to about 2400 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration.

[001654] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a fixed dosage of pirfenidone or a pirfenidone analog of about 800 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration.

[001655] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 1000 mg to about 1800 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 nig/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration.

[001656] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist and a SAPK inhibitor in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a fixed dosage of pirfenidone or a pirfenidone analog of about 1200 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration.

4f. VEGF antagonist, SAPK inhibitor, and a Type II interferon receptor agonist, in combination therapy to treat proliferative disorders [001657] Any of the above combination therapies using a VEGF antagonist and a SAPK inhibitor can be modified to include administration of a Type II interferon receptor agonist. In many embodiments, the Type II interferon receptor agonist is IFN-y. In certain embodiments, the IFN-y is Actimmune&commat; human IFN-ylb.

[001658] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; a dosage of a SAPK inhibitor containing an amount of from about 0.1 pg to about 3600 mg per dose, or from about 0.1 mg/kg to about 10 mg/kg per dose subcutaneously, intravenously, or orally qd, qod, tiw, or biw, or per day for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 llg to about 300, ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[001659] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 llg to about 300 ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[001660] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300mg/m2 per day subcutaneously, for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 ug to about 300 ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[001661] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/lcg of body weight to about 125 mg/kg of body weight, administered orally qd for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 zig to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[001662] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (Avastinrm) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration; a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 u. g to about 300 Ag of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[001663] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist as in any one of the above- described treatment regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described treatment regimens; and a dosage of IFN-y containing an amount of from about 10 u. g to about 300 vag of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.

[001664] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of a VEGF antagonist as in any one of the above- described treatment regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described treatment regimens; and a dosage of IFN-y containing an amount of from about 50 u, g to about 200 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously for the desired treatment duration.- [001665] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of SU5416 containing an amount of 145 mg/m intravenously twice weekly for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration ; and a dosage of IFN-y containing an amount of from about 10 u. g to about 300, ug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001666] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of SU6668 containing an amount of 300 mg/m2 orally twice daily for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 u, g to about 300 lug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001667] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily for the desired treatment duration ; a dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration ; and a dosage of IFN-y containing an amount of from about 10 Fg to about 300 n. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001668] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 wu to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001669] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of bevacizumab (Avastin) containing an amount of 5 mg/kg, 7.5 mg/kg, 10 mg/kg, or 15 mg/kg intravenously once every two weeks or once every three weeks for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 ig to about 300 wog of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001670] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of PTK787/ZK22584 containing an amount of 1500 mg/day orally for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 llg to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001671] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient a dosage of Angiozymew containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of IFN-&gamma; containing an amount of from about 10 ug to about 300 lug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001672] Any of the above-described treatment regimens featuring an IFN-&gamma; regimen can be modified such that the IFN-y is Actimmune (g) human IFN-ylb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 u. g, 50 u. g, 100 u. g, 150 u, g, or 200 ug.

[001673] Any of the above-described treatment regimens featuring a SAPK inhibitor regimen can be modified such that the SAPK inhibitor is pirfenidone or a pirfenidone analog, and is administered orally at a fixed dosage of 400 mg, 800 mg, 1000 mg, 1200 mg, 1600 mg, 1800 mg, 2400 mg, 3000 mg, or 3600 mg per day, optionally in two or more divided doses per day.

4g. VEGF antagonist, SAPK inhibitor, and a Type I interferon receptor agonist, in combination therapy to treat proliferative disorders [001674] Any of the above VEGF antagonist/SAPK inhibitor combination therapies can be modified to include administration of a Type I interferon receptor agonist. In many embodiments, the Type I interferon receptor agonist is IFN-a.

[001675] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and INFERGEN&commat;consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; and a dosage ofINFERGEN (R) containing an amount of about 1 llg to about 30 u. g, or about 9 ag to about 15 ag, of drug per dose of INFERGEN (D suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously for the desired treatment duration.

[001676] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and PEGylated consensus IFN-a (PEG-CIFN) in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; and a dosage of PEGylated consensus IFN-a (PEG- CIFN) containing an amount of about 10 Rg to about 100 wog, or about 40 Rg to about 80 ug, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly substantially continuously or continuously for the desired treatment duration.

[001677] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and IFN-a 2a, 2b or 2c in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; and a dosage of IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day for the desired treatment duration.

[001678] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and PEGASYS in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; and a dosage of PEGASYS (» containing an amount of about 90 u, g to about 360 u. g, or about 180 gg, of drug per dose of PEGASYSS subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

[001679] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and PEG-INTRO in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; and a dosage of PEG-INTRON (ít) containing an amount of about 0.75 llg to about 3.0 wog, or about 1. zug to about 1. 5 u, g, of drug per kilogram of body weight per dose of PEG- INTRO subcutaneously biw, qw, qow, three times per month, or monthly for the desired treatment duration.

[001680] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and mono PEG (30 kD, linear) -ylated consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; and a dosage of mono PEG (30 kD, linear)-ylated consensus IFN-a containing an amount of from about 100 gag to about 200 g, or about 150 u, g, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

4h. VEGF antagonist, SAPK inhibitor, Type II interferon receptor agonist, and a Type I interferon receptor agonist, in combination therapy to treat proliferative disorders- [001681] Any of the above VEGF antagonist/SAPK inhibitor combination therapies can be modified to include administration of a Type I interferon receptor agonist and a Type II interferon agonist. In many embodiments, the Type I interferon receptor agonist is IFN-a. In many embodiments, the Type II interferon receptor agonist is IFN-y.

[001682] Thus, in particular embodiments, the invention provides a combination therapy for the treatment of proliferative disorders, comprising administering a VEGF antagonist, a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts for the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient (a) a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinT, 4) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration ; (b) a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration ; (c) a dosage of IFN-containing an amount of from about 10 u. g to about 300 lug of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously ; and (d) a dosage of an IFN-a selected from the group consisting of (i) INFERGEN containing an amount of about 1 llg to about 30 u, g, or about 9 ug to about 15 u, g, of drug per dose of INFERGEN (g) suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 ug to about 100 Fg of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day (iv) PEGASYS (g containing an amount of about 90 llg to about 360 u, g, or about 180 u. g, of drug per dose of PEGASYS subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 u. g to about 3.0 Rg, or about 1.0 llg to about 1.5 u. g, of drug per kilogram of body weight per dose of PEG-INTRON (g) suboutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 wu to about 200 llg, or about 150 u. g, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration.

4i. VEGF antagonist, SAPK inhibitor, and TNF antagonist in combination therapy to treat proliferative disorders [001683] The invention provides combination therapy for the treatment of proliferative disorders, comprising administering a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in combined effective amounts to treat the proliferative disorder. In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; a dosage of a SAPK inhibitor containing an amount of from about 0.1 llg to about 3600 mg per dose, or from about 0.1 mg/kg to about 10 mg/kg per dose subcutaneously, intravenously, or orally qd, qod, tiw, or biw, or per day for the desired treatment duration; and a dosage of a TNF antagonist containing an amount of from about 0.1 u. g to about 40 mg per dose, or from about 0.1 mg/kg to about 10 mg/kg per dose subcutaneously, intravenously, or orally qd, qod, tiw, or biw, or per day for the desired treatment duration.

[001684] The invention provides combination therapy for the treatment of proliferative disorders, comprising administering a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in combined effective amounts to treat the proliferative disorder. In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration ; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF antagonist containing an amount of from about 0. 1 ug to about 40 mg per dose, or from about 0.1 mg/kg to about 10 mg/kg per dose subcutaneously, intravenously, or orally qd, qod, tiw, or biw, or per day for the desired treatment duration.

[001685] The invention provides combination therapy for the treatment of proliferative disorders, comprising administering a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in combined effective amounts to treat the proliferative disorder. In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001686] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of SU5416 containing an amount of 145 mg/m2 intravenously twice weekly for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEO in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001687] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of SU6668 containing an amount of 300 mg/m2 orally twice daily; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001688] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL (E) in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEO in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001689] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of ZD6474 containing an amount- of from about 100 mg/day to about 300 mg/day orally daily; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001690] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of bevacizumab (Avastin) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL (T in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADES in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001691] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of PTK787/ZK22584 containing an amount of about 1500 mg/day orally; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEt) in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001692] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of Angiozyme containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

4i. VEGF antagonist, SAPK inhibitor, Type II interferon receptor agonist, and TNF antagonist in combination therapy to treat proliferative disorders [001693] Any of the above combination therapies using a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist can be modified to include administration of a Type II interferon receptor agonist. In many embodiments, the Type II interferon receptor agonist is IFN-Y. In certain embodiments, the IFN-y is Actimmuneg human IFN-ylb.

[001694] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration ; a dosage of a SAPK inhibitor containing an amount of from about 0.1 llg to about 3600 mg per dose, or from about 0.1 mg/kg to about 10 mg/kg per dose subcutaneously, intravenously, or orally qd, qod, tiw, or biw, or per day for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 wu to about 300 Fg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001695] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and IFN-y in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-y containing an amount of from about 10 ug to about 300 jj, g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[001696] In any one of the above-described treatment regimens, the VEGF antagonist regimen can be replaced with a VEGF antagonist regimen selected from (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (AvastinTM) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mg/m2 per day subcutaneously, for the desired treatment duration.

[001697] Any of the above-described treatment regimens can be modified such that the IFN-y is Actimmune (g) human IFN-ylb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 n. g, 50 Rg, 100 u. g, 150 u, g, or 200 u. g.

4j. VEGF antagonist, SAPK inhibitor, Type I interferon receptor agonist, and TNF antagonist in combination therapy to treat proliferative disorders [001698] Any of the above combination therapies using a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist can be modified to include administration of a Type I interferon receptor agonist.

[001699] In particular embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and a Type I interferon receptor agonist in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co-administering to the patient a dosage of a VEGF antagonist containing an amount of from about 10 mg to about 1500 mg, from about 10 mg/m2 to about 500 mg/m2, or from about 5 mg/kg to about 200 mg/kg, subcutaneously, intravenously, or orally qd, qod, tiw, or biw, once every two weeks, once every three weeks, or per day for the desired treatment duration; a dosage of a SAPK inhibitor containing an amount of from about 0. 1 u. g to about 3600 mg per dose, or from about 0.1 mg/kg to about 10 mg/kg per dose subcutaneously, intravenously, or orally qd,-qod, tiw, or biw, or per day for the desired treatment duration; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL (M in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (t in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-a containing an effective amount of IFN-a administered subcutaneously at a desired frequency and for the desired treatment duration.

[001700] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and INFERGEN&commat;consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; a dosage. of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of INFERGEN (t containing an amount of about 1 wu to about 30 fig, or about 9 ug to about 15 p. g, of drug per dose of INFERGEN subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously for the desired treatment duration.

[001701] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and PEGylated consensus IFN-a (PEG- CIFN) in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 wu to about 100 gg, or about 40 ug to about 80 ug, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly substantially continuously or continuously for the desired treatment duration.

[001702] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and IFN-a 2a, 2b or 2c in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL&commat; in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day for the desired treatment duration.

[001703] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and PEGASYS in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADES in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of PEGASYS containing an amount of about 90 g to about 360, ug, or about 180 gg, of drug per dose of PEGASYS (» subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

[001704] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and PEG-INTRON in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (t in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of PEU-INTRO containing an amount of about 0.75 wu to about 3.0 fig, or about 1. zig to about 1.5 u. g, of drug per kilogram of body weight per dose of PEG-INTRON (g) subcutaneously biw, qw, qow, three times per month, or monthly for the desired treatment duration.

[001705] In some embodiments, the invention provides a method using an effective amount of a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, and mono PEG (30 kD, linear)-ylated consensus IFN-a in the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising administering to the patient a dosage of a VEGF antagonist as in any of the above-described regimens; a dosage of pirfenidone or a pirfenidone analog as in any one of the above-described regimens; a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADES in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 llg to about 200 u. g, or about 150 u. g, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration.

4k. VEGF antagonist, SAPK inhibitor, Type I interferon receptor agonist, Type II interferon receptor agonist, and TNF antagonist in combination therapy to treat proliferative disorders [001706] Any of the above combination therapies using a VEGF antagonist, a SAPK inhibitor, and a TNF antagonist can be modified to include administration of a Type I interferon receptor agonist and a Type II interferon agonist. In many embodiments, the Type I interferon receptor agonist is IFN-a. In many embodiments, the Type II interferon receptor agonist is IFN-y.

[001707] Thus, in particular embodiments, the invention provides a combination therapy for the treatment of proliferative disorders, comprising administering a VEGF antagonist, a SAPK inhibitor, a TNF antagonist, a Type II interferon receptor agonist, and a Type I interferon receptor agonist in combined effective amounts for the treatment of a proliferative disorder, including any fibrotic disorder, cancer, or angiogenic disease, in a patient, comprising co- administering to the patient (a) a dosage of a VEGF antagonist selected from the group consisting of (i) SU5416 containing an amount of 145 mg/m2 intravenously twice weekly (ii) SU6668 containing an amount of 300 mg/m2 orally twice daily (iii) ZD4190 containing an amount of from about 12.5 mg/kg to about 100 mg/kg orally daily, (iv) ZD6474 containing an amount of from about 100 mg/day to about 300 mg/day orally daily (v) bevacizumab (Avastitirm) containing an amount of about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg intravenously once every two weeks or once every three weeks (vii) PTK787/ZK22584 containing an amount of about 1500 mg/day orally or (viii) AngiozymeTM containing an amount of from about 100 mg/m2 per day to about 300 mglm2 per day subcutaneously, for the desired treatment duration; (b) a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration; (c) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL# in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; (d) a dosage of IFN-y containing an amount of from about 10 ßg to about 300 p, g of drug per dose of IFN-, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and (e) a dosage of an IFN-a selected from the group consisting of (i) INFERGEN containing an amount of about 1 µg to about 30 p. g, or about 9 llg to about 15 ug, of drug per dose of INFERGEN# subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 u. g to about 100 ug, or about 40 ug to about 80 llg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day (iv) PEGASYS containing an amount of about 90 pg to about 360 u. g, or about 180, ut, of drug per dose of PEGASYS subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRO containing an amount of about 0.75 llg to about 3.0 u. g, or about 1.0 llg to about 1. 5 ug, of drug per kilogram of body weight per dose of PEG-INTRON# subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 gg to about 200 u, g, or about 150 gg, of drug per dose of mono PEG (30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration.

[001708] Any of the above-described treatment regimens can be modified such that the IFN-y is Actimmune human IFN-lb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 u. g, 50 u. g, 100 u. g, 150 u. g, or 200 u. g.

41. VEGF antagonist combination therapy as adjuvant therapy to treat proliferative disorders [001709] In some embodiments, the present invention provides methods for combination therapy using a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, where the VEGF antagonist and the TNF antagonist, or the VEGF antagonist and the SAPK inhibitor, are administered as adjuvant therapy to a standard cancer therapy. Standard cancer therapies include surgery (e. g. , surgical removal of cancerous tissue), radiation therapy, bone marrow transplantation, chemotherapeutic treatment, biological response modifier treatment, and certain combinations of the foregoing.

[001710] Radiation therapy includes, but is not limited to, x-rays or gamma rays that are delivered from either an externally applied source such as a beam, or by implantation of small radioactive sources.

[001711] Chemotherapeutic agents are non-peptidic (i. e. , non-proteinaceous) compounds that reduce proliferation of cancer cells, and encompass cytotoxic agents and cytostatic agents.

Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant (vinca) alkaloids, and steroid hormones.

[001712] Agents that act to reduce cellular proliferation are known in the art and widely used.

Such agents include alkylating agents, such as nitrogen mustards, nitrosoureas, ethylenimine derivatives, alkyl sulfonates, and triazenes, including, but not limited to, mechlorethamine, cyclophosphamide (CytoxanTM), melphalan (L-sarcolysin), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, dacarbazine, and temozolomide.

[001713] Antimetabolite agents include folic acid analogs, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, including, but not limited to, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine, 6-mercaptopurine (6-MP), pentostatin, 5-fluorouracil (5-FU), methotrexate, 10-propargyl-5, 8-dideazafolate (PDDF, CB3717), 5,8-dideazatetrahydrofolic acid (DDATHF), leucovorin, fludarabine phosphate, pentostatine, and gemcitabine.- [001714] Suitable natural products and their derivatives, (e. g. , vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), include, but are not limited to, Ara-C, paclitaxel (Taxol (g)), docetaxel (Taxotere (g)), deoxycoformycin, mitomycin-C, L- asparaginase, azathioprine; brequinar; alkaloids, e. g. vincristine, vinblastine, vinorelbine, vindesine, etc. ; podophyllotoxins, e. g. etoposide, teniposide, etc. ; antibiotics, e. g. anthracycline, daunorubicin hydrochloride (daunomycin, rubidomycin, cerubidine), idarubicin, doxorubicin, epirubicin and morpholino derivatives, etc. ; phenoxizone biscyclopeptides, e. g. dactinomycin; basic glycopeptides, e. g. bleomycin; anthraquinone glycosides, e. g. plicamycin (mithramycin); anthracenediones, e. g. mitoxantrone; azirinopyrrolo indolediones, e. g. mitomycin; macrocyclic immunosuppressants, e. g. cyclosporine, FK-506 (tacrolimus, prograf), rapamycin, etc. ; and the like.

[001715] Other anti-proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[001716] Microtubule affecting agents that have antiproliferative activity are also suitable for use and include, but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e. g. , NSC 33410), dolstatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol&commat;), Taxol&commat; derivatives, docetaxel (Taxotere (»), thiocolchicine (NSC 361792), trityl cysterin, vinblastine sulfate, vincristine sulfate, natural and synthetic epothilones including but not limited to, eopthilone A, epothilone B, discodermolide ; estramustine, nocodazole, and the like.

[001717] Hormone modulators and steroids (including synthetic analogs) that are suitable for use include, but are not limited to, adrenocorticosteroids, e. g. prednisone, dexamethasone, etc. ; estrogens and pregestins, e. g. hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estradiol, clomiphene, tamoxifen; etc. ; and adrenocortical suppressants, e. g. aminoglutethimide ; 17a-ethinylestradiol ; diethylstilbestrol, testosterone, fluoxymesterone, dromostanolone propionate, testolactone, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, Flutamide (Drogenil), Toremifene (Fareston), and Zoladexg. Estrogens stimulate proliferation and differentiation, therefore compounds that bind to the estrogen receptor are used to block this activity. Corticosteroids may inhibit T cell proliferation.

[001718] Other chemotherapeutic agents include metal complexes, e. g. cisplatin (cis-DDP), carboplatin, etc. ; ureas, e. g. hydroxyurea; and hydrazines, e. g. N-methylhydrazine; epidophyllotoxin; a topoisomerase inhibitor; procarbazine ; mitoxantrone; leucovorin; tegafur; etc.. Other anti-proliferative agents of interest include immunosuppressants, e. g. mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); Iressa (ZD 1839, 4- (3-chloro-4-fluorophenylamino)-7-methoxy-6- (3- (4-morpholinyl) propoxy) quinazoline) ; etc..

[001719]"Taxanes"include paclitaxel, as well as any active taxane derivative or pro-drug.

"Paclitaxel" (which should be understood herein to include analogues, formulations, and derivatives such as, for example, docetaxel, TAXOLTM, TAXOTERETM (a formulation of docetaxel), 10-desacetyl analogs of paclitaxel and 3N-desbenzoyl-3'N-t-butoxycarbonyl analogs of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see also WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076; U. S. Pat. Nos. 5,294, 637; 5,283, 253; 5,279, 949; 5,274, 137; 5,202, 448; 5,200, 534; 5,229, 529; and EP 590,267), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co. , St. Louis, Mo. (T7402 from Taxus brevifolia ; or T-1912 from Taxus yannanensis).

[001720] Paclitaxel should be understood to refer to not only the common chemically available form of paclitaxel, but analogs and derivatives (e. g., Taxotere docetaxel, as noted above) and paclitaxel conjugates (e. g. , paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylose).

[001721] Also included within the term"taxane"are a variety of known derivatives, including both hydrophilic derivatives, and hydrophobic derivatives. Taxane derivatives include, but not limited to, galactose and mannose derivatives described in International Patent Application No.

WO 99/18113; piperazino and other derivatives described in WO 99/14209; taxane derivatives described in WO 99/09021, WO 98/22451, and U. S. Patent No. 5,869, 680; 6-thio derivatives described in WO 98/28288; sulfenamide derivatives described in U. S. Patent No. 5, 821, 263; and taxol derivative described in U. S. Patent No. 5,415, 869. It further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98/58927; WO 98/13059 ; and U. S. Patent No. 5,824, 701.

[001722] Biological response modifiers suitable for use in connection with the methods of the invention include, but are not limited to, (1) inhibitors of tyrosine kinase (RTK) activity; (2) inhibitors of serine/threonine kinase activity; (3) tumor-associated antigen antagonists, such as antibodies that bind specifically to a tumor antigen; (4) apoptosis receptor agonists; (5) interleuliin-2 ; (6) IFN-a ; (7) IFN-y (8) colony-stimulating factors; and (9) inhibitors of angiogenesis.

[001723] In one aspect, the invention contemplates VEGF antagonist/TNF antagonist combination therapy, or VEGF antagonist/SAPK inhibitor combination therapy, as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor, such as type I receptor tyrosine kinase inhibitors (e. g. , inhibitors of epidermal growth factor receptors), type II receptor tyrosine kinase inhibitors (e. g. , inhibitors of insulin receptor), type III receptor tyrosine kinase inhibitors (e. g. , inhibitors of platelet-derived growth factor receptor), and type IV receptor tyrosine kinase inhibitors (e. g. , fibroblast growth factor receptor). In other embodiments, the tyrosine kinase inhibitor is a non-receptor tyrosine kinase inhibitor, such as inhibitors of src kinases or janus kinases.

[001724] In another aspect, the invention contemplates VEGF antagonist/TNF antagonist combination therapy, or VEGF antagonist/SAPK inhibitor combination therapy, as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of a receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is genistein. In other embodiments, the inhibitor is an EGFR tyrosine kinase-specific antagonist, such as IRESSATM gefitinib (ZD18398; Novartis), TARCEVATM erolotinib (OSI-774; Roche; Genentech; OSI Pharmaceuticals), or tyrphostin AG1478 (4- (3-chloroanilino)-6, 7- dimethoxyquinazoline. In still other embodiments, the inhibitor is any indolinone antagonist of Flk-1/KDR (VEGF-R2) tyrosine kinase activity described in U. S. Patent Application Publication No. 2002/0183364 Al, such as the indolinone antagonists of Flk-1/KDR (VEGF- R2) tyrosine kinase activity disclosed in Table 1 on pages 4-5 thereof. In further embodiments, the inhibitor is any of the substituted 3- [ (4, 5,6, 7-tetrahydro-lH-indol-2-yl) methylene]-1, 3- dihydroindol-2-one antagonists of Flk-l/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity disclosed in Sun, L. , et al. , J. Med. Chem. j 43 (14) : 2655-2663 (2000). In additional embodiments, the inhibitor is any substituted 3- [ (3- or 4-carboxyethylpyrrol-2-yl) methylidenyl] indolin-2-one antagonist of Flt-1 (VEGF-Rl), Flk-1/KDR (VEGF-R2), FGF-R1 or PDGF-R tyrosine kinase activity disclosed in Sun, L. , et al. , J. Med. Chem., 42 (25) : 5120- 5130 (1999).

[001725] In another aspect, the invention contemplates VEGF antagonist/TNF antagonist combination therapy, or VEGF antagonist/SAPK inhibitor combination therapy, as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of a non-receptor tyrosine kinase involved in growth factor signaling pathway (s). In some embodiments, the inhibitor is an antagonist of JAK2 tyrosine kinase activity, such as tyrphostin AG490 (2-cyano-3- (3, 4- dihydroxyphenyl)-N-(benzyl)-2-propenamide). In other embodiments, the inhibitor is an antagonist of bor-abl tyròsine kinase activity, such as GLEEVECTMimatinib mesylate (STI- 571 ; Novartis).

[001726] In another aspect, the invention contemplates VEGF antagonist/TNF antagonist combination therapy, or VEGF antagonist/SAPK inhibitor combination therapy, as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a serine/threonine kinase inhibitor. In some embodiments, the serine/threonine kinase inhibitor is a receptor serine/threonine kinase inhibitor, such as antagonists of TGF-p receptor serine/threonine kinase activity. In other embodiments, the serine/threonine kinase inhibitor is a non-receptor serine/threonine kinase inhibitor, such as antagonists of the serine/threonine kinase activity of the MAP kinases, protein kinase C (PKC), protein kinase A (PKA), or the cyclin-dependent kinases (CDKs).

[001727] In another aspect, the invention contemplates VEGF antagonist/TNF antagonist combination therapy, or VEGF antagonist/SAPK inhibitor combination therapy, as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an inhibitor of one or more kinases involved in cell cycle regulation. In some embodiments, the inhibitor is an antagonist of CDK2 activation, such as tryphostin AG490 (2-cyano-3- (3, 4-dihydroxyphenyl)-N- (benzyl)-2- propenamide). In other embodiments, the inhibitor is an antagonist of CDKl/cyclin B activity, such as alsterpaullone. In still other embodiments, the inhibitor is an antagonist of CDK2 kinase activity, such as indirubin-3'-monoxime. In additional embodiments, the inhibitor is an ATP pool antagonist, such as lometrexol (described in U. S. Patent Application Publication No.

2002/0156023 Al).

[001728] In another aspect, the invention contemplates VEGF antagonist/TNF antagonist combination therapy, or VEGF antagonist/SAPK inhibitor combination therapy, as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an a tumor-associated antigen antagonist, such as an antibody antagonist. In some embodiments involving the treatment of HER2-expressing tumors, the tumor-associated antigen antagonist is an anti-HER2 monoclonal antibody, such as HERCEPTINTM trastuzumab. In some embodiments involving the treatment of CD20- expressing tumors, such as B-cell lymphomas, the tumor-associated antigen antagonist is an anti-CD20 monoclonal antibody, such as RITUXANTM rituximab.

[001729] In another aspect, the invention contemplates VEGF antagonist/TNF antagonist combination therapy, or VEGF antagonist/SAPK inhibitor combination therapy, as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is a tumor growth factor antagonist. In some embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor (EGF), such as an anti-EGF monoclonal antibody. In other embodiments, the tumor growth factor antagonist is an antagonist of epidermal growth factor receptor erbB 1 (EGFR), such as an anti-EGFR monoclonal antibody inhibitor of EGFR activation or signal transduction.

[001730] In another aspect, the invention contemplates VEGF antagonist/TNF antagonist combination therapy, or VEGF antagonist/SAPK inhibitor combination therapy, as an adjuvant to any therapy in which the cancer patient receives treatment with least one additional antineoplastic drug, where the additional drug is an Apo-2 ligand agonist. In some embodiments, the Apo-2 ligand agonist is any of the Apo-2 ligand polypeptides described in WO 97/25428.

[001731] Exemplary non-limiting examples of combination therapies that include treatment with radiation and a combination of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor ; or treatment with an additional chemotherapeutic agent and a combination of a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor, are as follows: [001732] 1) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; and cisplatin in a dosage range of from about 5 mg/m2 to about 150 mg/m2 ; [001733] 2) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; and carboplatin in a dosage range of from about 5 mg/m2 to about 1000 mg/m2 ; [001734] 3) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; and radiation in a dosage range of from about 200 cGy to about 8000 cGy ; [001735] 4) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; and paclitaxel in a dosage range of from about 40 mg/m2 to about 250 mg/m2 ; [001736] 5) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and-a SAPK inhibitor; and carboplatin in a dosage range of from about 5 mg/m2 to about 1000 mg/m2 ; [001737] 6) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; and leucovorin in a dosage range of from about 5 mg/m2 to about 1000 mg/m2 ; [001738] 7) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; and trastuzumab in an initial loading dose of 4 mg/kg and a weekly maintenance dose of 2 mg/kg; [001739] 8) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; trastuzumab in an initial loading dose of 4 mg/kg and a weekly maintenance dose of 2 mg/kg; and paclitaxel in a dosage range of from about 40 mg/m2 to about 250 mg/m2 ; [001740] 9) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; paclitaxel in a dosage range of from about 40 mg/m2 to about 250 mg/m2 ; and estramustine phosphate (Emoyte&commat;) in a dosage range of from about 5 mg/m2 to about 1000 mg/m2 ; [001741] 10) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; and 5FU in a dosage range of from about 5 mg/m2 to about 5000 mg/m2 ; [001742] 11) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; 5FU in a dosage range of from about 5 mg/m2 to about 5000 mg/m2 ; and radiation in a dose of from about 200 cGy to about 8000 cGy; [001743] 12) any of the above-described treatment regimens comprising administering a VEGF antagonist and a TNF antagonist, or a VEGF antagonist and a SAPK inhibitor; 5FU in a dosage range of from about 5 mg/m2 to about 5000 mg/m2 ; and paclitaxel in a dosage range of from about 40 mg/m2 to about 250 mg/m2.

4m. VEGF antagonist combination therapy, including a side effect management agent, to treat proliferative disorders [001744] Any of the above combination therapies can be modified to include administration of a side effect management agent. For example, any of the above-described combination therapies can be modified to include administration of acetaminophen, ibuprofen, or other NSAID, an H2 blocker, or an antacid.

TREATMENT OF FIBROTIC DISORDERS [001745] The present invention further provides methods of treating fibrotic disorders. In some embodiments, the methods involve administering a Type I interferon receptor agonist, a Type II interferon receptor agonist; and a tumor necrosis factor (TNF) antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a TNF antagonist. In other embodiments, the methods involve administering pirfenidone or a pirfenidone analog and a TNF antagonist. In other embodiments, the methods involve administering a Type II interferon receptor agonist and a transformining growth factor-beta (TGF-D) antagonist. In other embodiments, the methods involve administering a SAPK inhibitor alone or in combination with a Type II interferon receptor agonist. In other embodiments, the methods involve administering N-acetyl cysteine (NAC) and a SAPK inhibitor. In other embodiments, the methods involve administering NAC and a Type II interferon receptor agonist.

5) Type I or Type III interferon receptor agonist, Type II interferon receptor agonist, and TNF antagonist m combination therapy to treat fibrotic disorders [001746] In connection with each of the methods described herein, the invention provides embodiments in which an active agent (e. g. , a Type I or III interferon receptor agonist, a Type II interferon receptor agonist, a TNF-a antagonist, etc. ) is administered to the patient by a controlled drug delivery device. In some embodiments, the active agent is delivered to the patient substantially continuously or continuously by the controlled drug delivery device.

Optionally, an implantable infusion pump is used to deliver the active agent to the patient substantially continuously or continuously by subcutaneous infusion.

[001747] In other embodiments, an active agent (e. g. , a Type I or III interferon receptor agonist, a Type II interferon receptor agonist, a TNF-a antagonist, etc. ) is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the active agent at a substantially steady state for the duration of a subject therapy. Optionally, an implantable infusion pump is used to deliver the active agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the active agent at a substantially steady state for the duration of the subject therapy.

[001748] In some embodiments, the Type II interferon receptor agonist is an IFN-y.

[001749] Effective dosages of IFN-y can range from about 0.5 llg/m2 to about 500 ug/m2, usually from about 1. 5, ug/m2 to 200 pg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 u. g of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously.

[001750] In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 µg to about 500 ug, *om about 50 µg to about 400 µg, or from about 100 µg to about 300 Rg. In particular embodiments of interest, the dose is about 200 llg IFN-&gamma;. In many embodiments of interest, IFN-ylb is administered.

[001751] Where the dosage is 200 µg IFN-&gamma; per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 pg IFN-y per kg body weight to about 1. 48 ug IFN-per kg body weight.

[001752] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 µg/m2 to about 20 µg/m2. For example, an IFN-y dosage ranges from about 20 pg/m2 to about 30 µg/m2, from about 30 ug/m2 to about 40 Rg/m2, from about 40 Fg/m2 to about 50 µg/m2, from about 50 Fg/m2 to about 60 µg/m2, from about 60 llg/m2 to about 70 µg/m2, from about 70 µg/m2 to about 80 µg/m2, from about 80 µg/m2 to about 90 µg/m2, from about 90 µg/m2 to about 100 µg/m2, from about 100 ug/m2to about 110 µg/m2, from about 110 µg/m2 to about 120 µg/m2, from about 120 µg/m2 to about 130 µg/m2, from about 130 pg/m2 to about 140 µg/m2, or from about 140 llg/m2 to about 150 llg/m2. In some embodiments, the dosage groups range from about 25 µg/m2 to about 100 Rg/m2. In other embodiments, the dosage groups range from about 25 ug/m2 to about 50 µg/m2.

[001753] A Type I or III interferon receptor agonist can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001754] In some embodiments, the Type I or III interferon receptor agonist is an IFN-a.

Effective dosages of an IFN-a can range from about 1 µg to about 30 pug, from about 3 µg to about 27 µg, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 llg to about 180 u. g, or from about 18 llg to about 90 µg.

[001755] Effective dosages of InfergenX) consensus IFN-a include about 3 u. g, about 9 µg, about 15 µg, about 18 gg, or about 27 vug of drug per dose. Effective dosages of IFN-&alpha;2a and IFN- a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 llg to 180 u. g, or about 135 µg, of drug per dose.

Effective dosages of PEGylated IFN-a2b can contain an amount of about 0. 5 u. g to 1. 5 u. g of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 18 µg to about 90 u, g, or from about 27 pLg to about 60 µg, or about 45 µg, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001756] In some embodiments, a Type I or III interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen. The first dosing regimen of Type I or III interferon receptor agonist (also referred to as"the induction regimen") generally involves administration of a higher dosage of the Type I or III interferon receptor agonist. For example, in the case of Infergen (I consensus IFN-A (CIFN), the first dosing regimen comprises administering CIFN at about 9 ug, about 15 Zg, about 18 gag, or about 27 u, g. The first dosing regimen can encompass a single dosing event, or at least two or more dosing events. The first dosing regimen of the Type I or III interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001757] The first dosing regimen of the Type I or III interferon receptor agonist is administered for a first period of time, which time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.

[001758] The second dosing regimen of the Type I or III interferon receptor agonist (also referred to as"the maintenance dose") generally involves administration of a lower amount of the Type I or III interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CIFN at least about 3 u. g, at least about 9 u. g, at least about 15 u. g, or at least about 18 u. g. The second dosing regimen can encompass a single dosing event, or at least two or more dosing events.

[001759] The second dosing regimen of the Type I or III interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001760] In some embodiments, where an"induction"/"maintenance"dosing regimen of a Type I or a III interferon receptor agonist is administered, a"priming"dose of a Type II interferon receptor agonist is included. In these embodiments, Type II interferon receptor agonist can be administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or III interferon receptor agonist. This period of time is referred to as the"priming" phase. In some of these embodiments, Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or III interferon receptor agonist. In other embodiments, Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or III interferon receptor agonist.

[001761] In other embodiments, the Type I or III interferon receptor agonist is administered in a non-induction (single) dosing regimen. For example, in the case of CIFN, the dose of CIFN is generally in a range of from about 3 ug to about 15 ug, or from about 9 ug to about 15 ug. The dose of Type I or a Type III interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times per month, once monthly, or substantially continuously. The dose of the Type I or III interferon receptor agonist is administered for a period of time, which period can be, for example, from at least about 24 weeks to at least about 48 weeks, or longer.

[001762] In some embodiments, where a single dosing regimen of a Type I or III interferon receptor agonist is administered, a"priming"dose of Type II interferon receptor agonist is included. For example, a Type II interferon receptor agonist can be administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or III interferon receptor agonist. This period of time is referred to as the"priming"phase. In some of these embodiments, Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or III interferon receptor agonist. In other embodiments, Type II interferon receptor agonist treatment is discontinued before the end of treatment with Type I or III interferon receptor agonist. In some of these embodiments, the total time of treatment with the Type II interferon receptor agonist (including the"priming"phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days. In still other embodiments, Type II interferon receptor agonist treatment is discontinued once Type I or III interferon receptor agonist treatment begins.

[001763] Effective dosages of a TNF-a antagonist range from 0. 1, ug to 40 mg per dose, e. g., from about 0.1 Fg to about 0.5 u. g per dose, from about 0. 5, ug to about 1. 0, ug per dose, from about 1.0 llg per dose to about 5.0 llg per dose, from about 5. 0 wu to about 10 llg per dose, from about 10 ug to about 20 llg per dose, from about 20 ug per dose to about 30 Zg per dose, from about 30 pg per dose to about 40 ug per dose, from about 40 ug per dose to about 50 ug per dose, from about 50 ug per dose to about 60 zg per dose, from about 60 Fg per dose to about 70 ug per dose, from about 70 llg to about 80 Zg per dose, from about 80 u. g per dose to about 100 pg per dose, from about 100 gag to about 150 llg per dose, from about 150 gag to about 200 ug per dose, from about 200 llg per dose to about 250 llg per dose, from about 250 Ag to about 300 ug per dose, from about 300 µg to about 400 µg per dose, from about 400 ug to about 500 pg per dose, from about 500 llg to about 600 ug per dose, from about 600 u. g to about 700 llg per dose, from about 700 wu to about 800 jig per dose, from about 800 u. g to about 900 llg per dose, from about 900 llg to about 1000 u. g per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001764] In some embodiments, the TNF-a antagonist is ENBREL etanercept. Effective dosages of etanercept range from about 0. 1 gag to about 40 mg per dose, from about 0.1 tig to about 1 llg per dose, from about 1 u. g to about 10 jig per dose, from about 10 u. g to about 100 llg per dose, from about 100 llg to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001765] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[001766] In some embodiments, the TNF-a antagonist is REMICADE (g). Effective dosages of REMICADE range from about about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4. 5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[001767] In some embodiments the TNF-a antagonist is HUMIRATM. Effective dosages of HUMIRATM range from about 0. 1 lug to about 35 mg, from about 0.1 tig to about 1 jig, from about 1 Rg to about 10 pg, from about 10 u. g to about 100 u. g, from about 100 Rg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[001768] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[001769] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001770] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[001771] In some embodiments, the Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the Type I or III interferon receptor agonist, Type II interferon receptor agonist and/or TNF-a antagonist are administered separately, e. g. , in separate formulations. In some of these embodiments, the Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist are administered separately, and are administered simultaneously. In other embodiments, the Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[001772] Multiple doses of a Type I or III interferon receptor agonist, Type II interferon receptor agonist and/or TNF-a antagonist can be administered, e. g. , the Type I or III interferon receptor agonist, Type II interferon receptor agonist and/or TNF-a antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001773] In some embodiments, where Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist are administered in combination therapy, the three drugs are co-formulated in a single liquid formulation that is contained in a single reservoir, for use in a drug delivery device. Thus, the present invention provides a pharmaceutical formulation comprising a liquid formulation comprising a single dose of Type I or III interferon receptor agonist, a single dose of Type II interferon receptor agonist, and a single dose of TNF-a antagonist. Thus, the present invention provides a drug reservoir or other container containing Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist co-formulated in a liquid, wherein the three drugs are present in the formulation in an amount suitable for one dose each. Dosage amounts are described herein. The reservoir can be provided in any of a variety of forms, including, but not limited to, a cartridge, a syringe, a reservoir of a continuous delivery device, and the like. The invention further provides a drug delivery device comprising (e. g. , pre-loaded with) a reservoir containing a liquid formulation that comprises a single dose of Type I or III interferon receptor agonist, a single dose of Type II interferon receptor agonist, and a single dose of TNF-a antagonist. Exemplary, non-limiting drug delivery devices include injection devices, such as pen injectors, needle/syringe devices, continuous delivery devices, and the like. Any of the dosage amounts, including synergistically effective amounts, described herein can be used in the pharmaceutical formulation, in the reservoir, or in the drug delivery device.

[001774] In other embodiments, where Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist are administered in combination therapy, each of the three drugs is in a pharmaceutical formulation contained in a separate reservoir in the same drug delivery device. The invention further provides a drug delivery device that is pre-loaded with separate reservoirs, one reservoir containing a liquid formulation comprising a single dose of Type I or III interferon receptor agonist, and a second reservoir containing a liquid formulation comprising a single dose of Type II interferon receptor agonist, and a third reservoir containing a liquid formulation comprising a single dose of a TNF-a antagonist. Any of the dosage amounts, including synergistically effective amounts, described herein can be used in the pharmaceutical formulation, in the reservoir, or in the drug delivery device.

[001775] In some embodiments, in a treatment method described herein, the Type I or III interferon receptor agonist is an IFN-a, the Type II interferon receptor agonist is an IFN-y, and the subject method comprises co-administering to the patient an effective amount of IFN-y for the duration of the IFN-a therapy. In one embodiment, the IFN-y is administered to the patient by bolus injection. In another embodiment, the IFN-a and IFN-y are administered to the patient by a drug delivery device. Optionally, the device is used to deliver the IFN-a to the patient by substantially continuous or continuous administration and used to deliver the IFN-y to the patient by bolus administration tiw, biw, qod, or qd. Optionally, the device is used to deliver the IFN-a and IFN-y to the patient in the same manner and pattern of administration, such as substantially continuous or continuous administration. Optionally, the IFN-a and IFN- y are contained in separate reservoirs in the drug delivery device. Optionally, the IFN-a and IFN-y are co-formulated in a single liquid formulation that is contained in a single reservoir in the drug delivery device.

5a. Additional therapeutic agents for use in Type I or Type III interferon receptor agonist, Type II interferon receptor agonist, and TNF antagonist combination therapy to treat fibrotic disorders [001776] In some embodiments, the method further includes administration of pirfenidone or a pirfenidone analog. Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001777] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos., 5,310, 562; 5,518, 729 ; 5,716, 632 ; and 6, 090, 822.

[0017781 In some embodiments, pirfenidone or a pirfenidone analog is administered throughout the entire course of Type I or III interferon receptor agonist, Type II interferon receptor agonist, or TNF-a antagonist treatment. In other embodiments, pirfenidone or a pirfenidone analog is administered less than the entire course of Type I or III interferon receptor agonist, Type II interferon receptor agonist, or TNF-a antagonist treatment, e. g. , only during the first phase of Type I or III interferon receptor agonist, Type II interferon receptor agonist, or TNF-a antagonist treatment, only during the second phase of Type I or III interferon receptor agonist, Type II interferon receptor agonist, or TNF-a antagonist treatment, or some other portion of the Type I or III interferon receptor agonist, Type II interferon receptor agonist, or TNF-a antagonist treatment regimen.- 5b. Type I or Type III interferon receptor agonist, Type II interferon receptor agonist, and TNF antagonist in combination therapy to treat fibrotic disorders [001779] In one aspect, the invention provides a method of treating fibrosis in a patient comprising administering to the patient an amount of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist and a TNF-a antagonist effective to reduce fibrosis or reduce the rate of progression of fibrotic disease. Optionally, the method of the invention provides for administering to the patient the combination of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist and a TNF-a antagonist, along with an amount of pirfenidone or a pirfenidone analog effective to enhance the anti-fibrotic effect or the reduction of fibrosis achieved by the Type I or III interferon receptor agonist, Type II interferon receptor agonist and TNF-a antagonist therapy.

[001780] In another aspect, the invention provides a method of increasing function in an organ affected by fibrosis in a patient, comprising administering to the patient an amount of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist, and a TNF-a antagonist effective to increase function of the affected organ. Optionally, the method of the invention provides for administering to the patient the combination of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist and a TNF-a antagonist, along with an amount of pirfenidone or a pirfenidone analog effective to enhance the anti-fibrotic effect or the increase in function of the affected organ achieved by the Type I or III interferon receptor agonist, Type II interferon receptor agonist and TNF-a antagonist therapy.

[001781] In another aspect, the invention provides a method of reducing the incidence of a complication of cirrhosis of the liver in a patient suffering from liver fibrosis, comprising administering to the patient an amount of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist and a TNF-a antagonist effective to reduce the incidence of a complication of cirrhosis of the liver. Optionally, the method of the invention provides for administering to the patient the combination of a Type I or III interferon receptor agonist, a Type II interferon receptor agonist and a TNF-a antagonist, along with an amount of pirfenidone or a pirfenidone analog effective to enhance the anti-fibrotic effect or the reduction of the incidence of a complication of cirrhosis of the liver achieved by the Type I or III interferon receptor agonist, Type II interferon receptor agonist and TNF-a antagonist therapy.

[001782] In some embodiments, the Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist are administered in the same formulation. In other embodiments, the Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist are administered in separate formulations. When administered in separate formulations, the Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist can be administered substantially simultaneously, or can be administered within about 24 hours of one another. In many embodiments, the Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist are administered subcutaneously in multiple doses.

[001783] In many embodiments, the Type I or III interferon receptor agonist, Type II interferon receptor agonist, or TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.

Dosage regimens can include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, and once bimonthly administrations.

[001784] In some embodiments, the invention provides methods using a synergistically effective amount of a Type I or III interferon receptor agonist, Type II interferon receptor agonist, and TNF-a antagonist in the treatment of fibrosis in a patient. In some embodiments, the invention provides methods using a synergistically effective amount of an IFN-a, IFN-y, and a TNF-a antagonist selected from the group consisting of ENBRELO, REMICADEV and HUMIRATM, in the treatment of fibrosis in a patient. In one embodiment, the invention provides a method using a synergistically effective amount of a consensus IFN-a, IFN-y, and a TNF-a antagonist selected from the group consisting of ENBRELS, REMICADEO and HUMIRATM, in the treatment of fibrosis in a patient.

[001785] In general, an effective amount of a consensus interferon (CIFN) and IFN-y suitable for use in the methods of the invention is provided by a dosage ratio of 1 ug CIFN : 10 zg IFN-, where both CIFN and IFN-y are unPEGylated and unglycosylated species.

[001786] In one embodiment, the invention provides a method using an effective amount of INFERGENt) consensus IFN-a, IFN-and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of INFERGENiE) containing an amount of about 1 u. g to about 30 ug, of drug per dose ofINFERGEN (R), subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, a dosage of IFN-y containing an amount of about 10 jig to about 300 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADES in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001787] In another embodiment, the invention provides a method using an effective amount of INFERGEN&commat;consensus IFN-a, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of INFERGENO containing an amount of about 1 u. g to about 9 gag, of drug per dose of INFERGENO, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, a dosage of IFN-y containing an amount of about 10 llg to about 100 u. g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001788] In another embodiment, the invention provides a method using an effective amount of INFERGEN (» consensus IFN-a, IFN-and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of INFERGEN (g) containing an amount of about 1 llg of drug per dose of INFERGENS, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, a dosage of IFN-y containing an amount of about 10 llg to about 50 llg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001789] In another embodiment, the invention provides a method using an effective amount of INFERGEN (» consensus IFN-a, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient comprising administering to the patient a dosage of INFERGEN (g) containing an amount of about 9 llg of drug per dose of INFERGENO, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, a dosage of IFN-y containing an amount of about 90 wu to about 100 gag of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001790] In another embodiment, the invention provides a method using an effective amount of INFERGEN (g) consensus IFN-a, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of INFERGENS containing an amount of about 30 llg of drug per dose of INFERGEN (», subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, a dosage of IFN-y containing an amount of about 200 µg to about 300 llg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001791] In another embodiment, the invention provides a method using an effective amount of PEGylated consensus IFN-a, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG- CIFN) containing an amount of about 4 Rg to about 60, ug of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, a total weekly dosage of IFN-y containing an amount of about 30 gag to about 1, 000 ug of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001792] In another embodiment, the invention provides a method using an effective amount of PEGylated consensus IFN-a, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG- CIFN) containing an amount of about zug to about 24 , g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, a total weekly dosage of IFN-y containing an amount of about 100 u, g to about 300 p. g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001793] In general, an effective amount of IFN-a 2a or 2b or 2c and IFN-y suitable for use in the methods of the invention is provided by a dosage ratio of 1 million Units (MU) IFN-a 2a or 2b or 2c: 30 ug IFN-y, where both IFN-a 2a or 2b or 2c and IFN-y are unPEGylated and unglycosylated species.

[001794] In another embodiment, the invention provides a method using an effective amount of IFN-a 2a or 2b or 2c, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of IFN-a2a containing an amount of about 1 MU to about 20 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, a dosage of IFN-y containing an amount of about 30 jj, g to about 600 ig of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001795] In another embodiment, the invention provides a method using an effective amount of IFN-a 2a or 2b or 2c, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of IFN-a2a containing an amount of about 3 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, a dosage of IFN-y containing an amount of about 100 jig of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADES in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001796] In another embodiment, the invention provides a method using an effective amount of IFN-a 2a or 2b or 2c, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of IFN-a2a containing an amount of about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, a dosage of IFN-y containing an amount of about 300 jj. g of drug per dose of IFN-, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADES in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001797] In another embodiment, the invention provides a method using an effective amount of PEGASYS (R) PEGylated IFN-a2a, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of PEGASYSW containing an amount of about 90 gag to about 3 60 gag, of drug per dose of PEGASYS (g), suboutaneously qw, qow, three times per month, or monthly, a total weekly dosage of IFN-y containing an amount of about 30 ig to about 1, 000) J, g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELS in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (R) in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001798] In another embodiment, the invention provides a method using an effective amount of PEGASYSOPEGylated IFN-a2a, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of PEGASYS (» containing an amount of about 180 u. g of drug per dose of PEGASYS, subcutaneously qw, qow, three times per month, or monthly, a total weekly dosage of IFN-y containing an amount of about 100 Ag to about 300 u. g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every-6 weeks, or once every 8 weeks, for the desired treatment duration.

[001799] In another embodiment, the invention provides a method using an effective amount of PEG-INTRON (» PEGylated IFN-a2b, IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of PEG-INTRON (» containing an amount of about 0. 75 u, g to about 3. 0 ug of drug per kilogram of body weight per dose of PEG- INTRONO, subcutaneously qw, qow, three times per month, or monthly, a total weekly dosage of IFN-y containing an amount of about 30 pg to about 1,000 ug of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001800] In another embodiment, the invention provides a method using an effective amount of PEG-INTRONPEGylated IFN-a2b, IFN-and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of PECi-INTRON (íD containing an amount of about 1.5 Zg of drug per kilogram of body weight per dose of PEG-INTRON (íD, subcutaneously qw, qow, three times per month, or monthly, a total weekly dosage of IFN-&gamma; containing an amount of about 160 tug to about 300 tig of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL) in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001801] The anti-fibrotic effect or other therapeutic benefit of such regimens can be enhanced by co-administering to the patient a weight-based dosage of pirfenidone or a specific pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 3600 mg, or about 800 mg to about 2400 mg, or about 1000 mg to about 1800 mg, or about 1200 mg to about 1600 mg, orally qd for the desired duration of Type I or III interferon receptor agonist, Type II interferon receptor agonist and TNF-a antagonist therapy.

[001802] In many embodiments, a Type I or III interferon receptor agonist, Type II interferon receptor agonist and/or TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. In embodiments utilizing co-administration of pirfenidone or a specific pirfenidone analog, the duration of therapy with pirfenidone or a specific pirfenidone analog can be coincident with the duration of therapy with Type I or III interferon receptor agonist, Type II interferon receptor agonist and/or TNF-a antagonist.

[001803] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of 9 pg INFERGEN consensus IFN-a administered subcutaneously qd or tiw; 50 ug Actimmunet) human IFN-ylb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE (»/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001804] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of 9 p. g INFERGEN consensus IFN-a administered subcutaneously tiw; 50 pg Actimmune (lt) human IFN-ylb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL (I administered subcutaneously biw (ii) 3 mg REMICADE (l)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001805] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 9 llg INFERGENO consensus IFN-a administered subcutaneously qd or tiw; 100 u. g Actimmune (E) human IFN-ylb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELS administered subcutaneously biw (ii) 3 mg REMICADE (»/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001806] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 9 ug INFERGEN consensus IFN-a administered subcutaneously tiw; 100 u. g Actimmune (g) human IFN-ylb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE (g)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001807] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of 9 llg INFERGEN consensus IFN-a administered subcutaneously qd or tiw; 25 . g Actimmune human IFN-ylb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL RO administered subcutaneously biw (ii) 3 mg REMICADE&commat;/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001808] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an-individual having a fibrotic disorder with a regimen of 9 ug INFERGEN consensus IFN-a administered subcutaneously tiw; 25 u, g Actimmune (B) human IFN-ylb administered subcutaneously tiw ; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELO administered subcutaneously biw (ii) 3 mg REMICADE (g)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001809] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of 9 pLg INFERGEN consensus IFN-a administered subcutaneously qd; 200 µg Actimmune# human IFN-ylb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL# administered subcutaneously biw (ii) 3 mg REMICADE (g)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001810] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of 9 gag INFERGEN# consensus IFN-a administered subcutaneously tiw; 200 llg Actimmune (t human IFN-&gamma;1b administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL (M administered subcutaneously biw (ii) 3 mg REMICADE#/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001811] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 llg monoPEG (30 kD, linear) -ylated consensus IFN-&alpha; administered subcutaneously every 10 days or qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELO administered subcutaneously biw (ii) 3 mg REMICADE&commat;/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 50 llg Actimmune human IFN-lb administered subcutaneously tiw; for the desired duration of therapy.

[001812] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 llg monoPEG (30 kD, linear)-ylated consensus IFN-a administered subcutaneously qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELS administered subcutaneously biw (ii) 3 mg REMICADE (íD/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 50 pg Actimmune# human IFN-ylb administered subcutaneously tiw; for the desired duration of therapy.

[001813] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 u. g monoPEG (30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE (g)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 100 yg Actimmune (g) human IFN-rlb administered subcutaneously tiw; for the desired duration of therapy.

[001814] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 ig monoPEG (30 kD, linear) -ylated consensus IFN-a administered subcutaneously qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE#/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 100 ßg Actimmune (g) human IFN-lb administered subcutaneously tiw; for the desired duration of therapy.

[001815] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 150 zg monoPEG (30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELO administered subcutaneously biw (ii) 3 mg REMICADEO/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 50 , g Actimmune human IFN-ylb administered subcutaneously tiw; for the desired duration of therapy.

[001816] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 150 u, g monoPEG (30 kD, linear)-ylated consensus IFN-a administered subcutaneously qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL (g) administered subcutaneously biw (ii) 3 mg REMICADES/kg patient body weight administered intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 50 ug ActimmuneOO human IFN-ylb administered subcutaneously tiw; for the desired duration of therapy.

[001817] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 150 llg monoPEG (30 kD, linear) -ylated consensus IFN-a administered subcutaneously every 10 days or qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELX administered subcutaneously biw (ii) 3 mg REMICADE (»/kg patient body weight administered intravenously at weeks 0, 2 and 6 ; and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 100 Fg Actimmune (D human IFN-ylb administered subcutaneously tiw; for the desired duration of therapy.

[001818] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 150 llg monoPEG (30 kD, linear) -ylated consensus IFN-a administered subcutaneously qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE (»/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 100, ug Actimmune (g) human IFN-lb administered subcutaneously tiw; for the desired duration of therapy.

[001819] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 200 g monoPEG (30 kD, linear) -ylated consensus IFN-a administered subcutaneously every 10 days or qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADES/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 50 µg Actimmune# human IFN-ylb administered subcutaneously tiw; for-the desired duration of therapy.

[001820] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 200 pg monoPEG (30 kD, linear) -ylated consensus IFN-a administered subcutaneously qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADEO/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 50 Fg Actimmune human IFN-ylb administered subcutaneously tiw; for the desired duration of therapy.

[001821] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 200 jig monoPEG (30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADES/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 100 ug Actimmune (g) human IFN-ylb administered subcutaneously tiw; for-the desired duration of therapy.

[001822] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 200 llg monoPEG (30 kD, linear) -ylated consensus IFN-a administered subcutaneously qw; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE&commat;/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; and 100 Fg Actimmunet) human IFN-ylb administered subcutaneously tiw; for the desired duration of therapy.

[0018231 Any of the above-described treatment regimens for treating a fibrotic disorder can be modified to include administering an effective amount of N-acetylcysteine (NAC).

[001824] Effective dosages of NAC can range from about 100 mg to about 1000 mg per day, or from about 100 mg to about 500 mg per day, or from about 500 mg to about 750 mg per day, or from about 750 mg to about 1000 mg per day, or from about 400 mg to about 3600 mg per day, or from about 800 mg to about 2400 mg per day, or from about 1000 mg to about 1800 mg per day, or from about 1200 mg to about 1600 mg per day.

[001825] NAC can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, three times per day, or in divided daily doses ranging from 2 to 5 times daily.

[001826] NAC can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001827] In some embodiments, NAC is administered throughout the entire course of the subject combination therapy. In other embodiments, NAC is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[001828] In some embodiments, NAC is administered at a dosage of NAC containing an amount of from about 500 mg to about 3000 mg of NAC per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration.

[001829] In some embodiments, NAC is administered at a dosage of 500 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001830] In other embodiments, NAC is administered at a dosage of 600 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001831] In other embodiments, NAC is administered at a dosage of 750 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001832] In other embodiments, NAC is administered at a dosage of 1000 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001833] 6) Type II interferon receptor agonist and TNF antagonist in combination therapy to treat fibrotic disorders [0018341 In connection with each of the methods described herein, the invention provides embodiments in which an active agent (e. g. , a Type II interferon receptor agonist, a TNF-a antagonist, etc. ) is administered to the patient by a controlled drug delivery device. In some embodiments, an active agent (e. g. , a Type II interferon receptor agonist, a TNF-a antagonist, etc. ) is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver an active agent (e. g. , a Type II interferon receptor agonist, a TNF-a antagonist, etc. ) to the patient substantially continuously or continuously by subcutaneous infusion.

[001835] In other embodiments, an active agent (e. g. , a Type II interferon receptor agonist, a TNF-a antagonist, etc. ) is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the active agent at a substantially steady state for the duration of the subject therapy. Optionally, an implantable infusion pump is used to deliver the active agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the active agent at a substantially steady state for the duration of the subject therapy.

[001836] In some embodiments, the Type II interferon receptor agonist is an IFN-y.

[001837] Effective dosages of IFN-y can range from about 0.5 llg/m2 to about 500 pg/m2, usually from about 1.5 llg/m2 to 200 llg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 llg of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously.

[001838] In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 llg to about 500 µg, from about 50 llg to about 400 µg, or from about 100 pg to about 300 u. g. In particular embodiments of interest, the dose is about 200 u. g IFN-&gamma;. In many embodiments of interest, IFN-y Ib is administered.

[001839] Where the dosage is 200 ug IFN-y per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4. 4 µg IFN-&gamma; per kg body weight to about 1.48 llg IFN-per kg body weight.

[001840] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 µg/m2 to about 20 gg/m2. For example, an IFN-&gamma; dosage ranges from about 20 pg/m2 to about 30 µg/m2, from about 30 Fg/m2 to about 40 µg/m2, from about 40 Zg/m2 to about 50 µg/m2, from about 50 µg/m2 to about 60, ug/m2, from about 60 pg/m2 to about 70 µg/m2, from about 70 Zg/m2 to about 80, ug/m2, from about 80 ug/m2 to about 90 Fg/m2, from about 90 µg/m2 to about 100 Rg/m2, from about 100 llg/m2to about 110 ßg/m2, from about 110 ug/m2 to about 120 µg/m2, from about 120 µg/m2 to about 130 Fg/m2, from about 130 µg/m2 to about 140 µg/m2, or from about 140 µg/m2 to about 150 µg/m2. In some embodiments, the dosage groups range from about 25 pg/m2 to about 100 µg/m2. In other embodiments, the dosage groups range from about 25 ug/m2 to about 50 µg/m2.

[001841] In many embodiments, IFN-y is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.

IFN-y can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[001842] In many embodiments, multiple doses of IFN-y are administered. For example, IFN-y is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001843] Effective dosages of a TNF-a antagonist range from 0. 1 ug to 40 mg per dose, e. g., from about 0. 1 ug to about 0.5 Uug per dose, from about 0.5 llg to about 1. zug per dose, from about 1. 0 pug per dose to about 5. 0 ug per dose, from about 5.0 u. g to about 10 llg per dose, from about 10 llg to about 20 µg per dose, from about 20 gag per dose to about 30 µg per dose, from about 30 u. g per dose to about 40 ug per dose, from about 40 llg per dose to about 50 µg per dose, from about 50 µg per dose to about 60 ug per dose, from about 60 u, g per dose to about 70 ug per dose, from about 70 Zg to about 80 llg per dose, from about 80 gg per dose to about 100 ug per dose, from about 100 u. g to about 150 llg per dose, from about 150 µg to about 200 u. g per dose, from about 200 llg per dose to about 250 ug per dose, from about 250 ßg to about 300 u, g per dose, from about 300 u. g to about 400 llg per dose, from about 400 llg to about 500 llg per dose, from about 500 llg to about 600 gag per dose, from about 600 u, g to about 700 u, g per dose, from about 700 llg to about 800 u, g per dose, from about 800 u. g to about 900 µg per dose, from about 900 llg to about 1000 gag per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001844] In some embodiments, the TNF-a antagonist is ENBREL# etanercept. Effective dosages of etanercept range from about 0. 1 µg to about 40 mg per dose, from about 0.1 llg to about 1 u, g per dose, from about 1 µg to about 10 llg per dose, from about 10 u. g to about 100 llg per dose, from about 100 ug to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001845] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g. , from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[001846] In some embodiments, the TNF-a antagonist is REMICADE (g). Effective dosages of REMICADE range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kgj *om about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[001847] In some embodiments the TNF-a antagonist is HUMIRATM. Effective dosages of HUMIRATM range from about 0. 1, ug to about 35 mg, from about 0.1 ßg to about 1 u, g, from about 1 ig to about 10 u. g, from about 10 ug to about 100 u. g, from about 100 llg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[001848] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, once bimonthly, substantially continuously, or continuously.

[001849] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once bimonthly, once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001850] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[001851] In some embodiments, the Type II interferon receptor agonist and TNF-a antagonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and/or TNF-a antagonist are administered separately, e. g. , in separate formulations. In some of these embodiments, the Type II interferon receptor agonist and TNF-a antagonist are administered separately, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and TNF-a antagonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[001852] Multiple doses of a Type II interferon receptor agonist and/or TNF-a antagonist can be administered, e. g. , the Type II interferon receptor agonist and/or TNF-a antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001853] In some embodiments, where Type II interferon receptor agonist and TNF-a antagonist are administered in combination therapy, both drugs are co-formulated in a single liquid formulation that is contained in a single reservoir, for use in a drug delivery device. Thus, the present invention provides a pharmaceutical formulation comprising a liquid formulation comprising a single dose of Type II interferon receptor agonist and a single dose of TNF-a antagonist. Thus, the present invention provides a drug reservoir or other container containing Type Il interferon receptor agonist and TNF-a antagonist co-formulated in a liquid, wherein both drugs are present in the formulation in an amount suitable for one dose each. Dosage amounts are described herein. The reservoir can be provided in any of a variety of forms, including, but not limited to, a cartridge, a syringe, a reservoir of a continuous delivery device, and the like. The invention further provides a drug delivery device comprising (e. g. , pre- loaded with) a reservoir containing a liquid formulation that comprises a single dose of Type II interferon receptor agonist and a single dose of TNF-a antagonist. Exemplary, non-limiting drug delivery devices include injection devices, such as pen injectors, needle/syringe devices, continuous delivery devices, and the like. Any of the dosage amounts, including synergistically effective amounts, described herein can be used in the pharmaceutical formulation, in the reservoir, or in the drug delivery device.

[001854] In other embodiments, where Type II interferon receptor agonist and TNF-a antagonist are administered in combination therapy, each of the drugs is in a pharmaceutical formulation contained in a separate reservoir in the same drug delivery device. The invention further provides a drug delivery device that is pre-loaded with separate reservoirs, one reservoir containing a liquid formulation comprising a single dose of Type II interferon receptor agonist, and a second reservoir containing a liquid formulation comprising a single dose of a TNF-a antagonist. Any of the dosage amounts, including synergistically effective amounts, described herein can be used in the pharmaceutical formulation, in the reservoir, or in the drug delivery device.

[001855] In some embodiments, in a treatment method described herein, the Type II interferon receptor agonist is an IFN-y, and the subject method comprises co-administering to the patient an effective amount of IFN-y for the duration of the TNF-a antagonist therapy. In one embodiment, the IFN-y is administered to the patient by bolus injection. In another embodiment, the TNF-a antagonist and IFN-y are administered to the patient by a drug delivery device. Optionally, the device is used to deliver the TNF-a antagonist to the patient by substantially continuous or continuous administration and used to deliver the IFN-y to the patient by bolus administration tiw, biw, qod, or qd. Optionally, the device is used to deliver the TNF-a antagonist and IFN-y to the patient in the same manner and pattern of administration, such as substantially continuous or continuous administration. Optionally, the TNF-a antagonist and IFN-y are contained in separate reservoirs in the drug delivery device.

Optionally, the TNF-a antagonist and IFN-y are co-formulated in a single liquid formulation that is contained in a single reservoir in the drug delivery device.

6a. Additional therapeutic agents for use in Type II interferon receptor agonist and TNF antagonist combination therapy to treat fibrotic disorders [001856] In some embodiments, the method further includes administration of pirfenidone or a pirfenidone analog. Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001857] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos., 5, 310, 562; 5, 518, 729; 5,716, 632; and 6,090, 822.

[001858] In some embodiments, pirfenidone or a pirfenidone analog is administered throughout the entire course of Type II interferon receptor agonist or TNF-a antagonist treatment. In other embodiments, pirfenidone or a pirfenidone analog is administered less than the entire course of Type Il interferon receptor agonist or TNF-a antagonist treatment, e. g. , only during the first phase of Type II interferon receptor agonist or TNF-a antagonist treatment, only during the second phase of Type II interferon receptor agonist or TNF-a antagonist treatment, or some other portion of the Type II interferon receptor agonist or TNF-a antagonist treatment regimen.

[001859] In some embodiments, the method further includes administration of a Type I or III interferon receptor agonist. A Type I or III interferon receptor agonist can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001860] In some embodiments, the Type I or III interferon receptor agonist is an IFN-a.

Effective dosages of an IFN-a can range from about 1 llg to about 30 gag, from about 3 llg to about 27 u. g, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 u. g to about 180, ut, or from about 18 u, g to about 90 u. g.

[001861] Effective dosages of Infergen&commat; consensus IFN-a include about 3 ßg, about 9, ug, about 15 u. g, about 18 u. g, or about 27 u, g of drug per dose. Effective dosages of IFN-a2a and IFN- a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 llg to 180 u. g, or about 135 u, g, of drug per dose.

Effective dosages of PEGylated IFN-a2b can contain an amount of about 0.5 fig to 1. 5 u, g of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 18 Ag to about 90 u. g, or from about 27 gag to about 60 u. g, or about 45 , g, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

6b. Type II interferon receptor agonist and TNF antagonist combination therapy to treat fibrotic disorders [001862] Individuals with fibrosis who are suitable for treatment according to the methods of the invention include individuals who have been clinically diagnosed with fibrosis, as well as individuals who have not yet developed clinical fibrosis but who are considered at risk of developing fibrosis.

[001863] In one aspect, the invention provides a method of treating fibrosis in a patient comprising administering to the patient an amount of a Type II interferon receptor agonist and TNF-a antagonist effective to reduce fibrosis or reduce the rate of progression of fibrotic disease. Optionally, the method of the invention provides for administering to the patient the Type II interferon receptor agonist and TNF-a antagonist along with an amount of pirfenidone or a pirfenidone analog effective to enhance the anti-fibrotic effect or the reduction of fibrosis achieved by the Type II interferon receptor agonist and TNF-a antagonist therapy.

[001864] In another aspect, the invention provides a method of increasing function in an organ affected by fibrosis in a patient, comprising administering to the patient an amount of a Type II interferon receptor agonist and TNF-a antagonist effective to increase function of the affected organ. Optionally, the method of the invention provides for administering to the patient the combination of a Type II-interferon receptor agonist and TNF-a antagonist along with an amount of pirfenidone or a pirfenidone analog effective to enhance the anti-fibrotic effect or the increase in function of the affected organ achieved by the Type II interferon receptor agonist and TNF-a antagonist therapy.

[001865] In another aspect, the invention provides a method of reducing the incidence of a complication of cirrhosis of the liver in a patient suffering from liver fibrosis, comprising administering to the patient an amount of a Type II interferon receptor agonist and TNF-a antagonist effective to reduce the incidence of a complication of cirrhosis of the liver.

Optionally, the method of the invention provides for administering to the patient the combination of a Type II interferon receptor agonist and TNF-a antagonist along with an amount of pirfenidone or a pirfenidone analog effective to enhance the anti-fibrotic effect or the reduction of the incidence of a complication of cirrhosis of the liver achieved by the Type II interferon receptor agonist and TNF-a antagonist therapy.

[001866] In some embodiments, the Type II interferon receptor agonist and TNF-a antagonist are administered in the same formulation. In other embodiments, the Type II interferon receptor agonist and TNF-a antagonist are administered in separate formulations. When administered in separate formulations, the Type II interferon receptor agonist and TNF-a antagonist can be administered substantially simultaneously, or can be administered within about 24 hours of one another. In many embodiments, the Type II interferon receptor agonist and TNF-a antagonist are administered subcutaneously in multiple doses.

[001867] In many embodiments, the Type II interferon receptor agonist or TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. Dosage regimens can include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, and once bimonthly administrations.

[001868] In some embodiments, the invention provides methods using a synergistically effective amount of a Type II interferon receptor agonist and TNF-a antagonist in the treatment of fibrosis in a patient. In some embodiments, the invention provides methods using a synergistically effective amount of IFN-and a TNF-a antagonist selected from the group consisting of ENBREL (g), REMICADEX and HUMIRATM, in the treatment of fibrosis in a patient.

[001869] In one embodiment, the invention provides a method using an effective amount of IFN- y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of IFN-y containing an amount of about 10 u. g to about 300 lug of drug per dose of IFN-y subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (E) in an amount of about 3 mg/kg to about 10 mg/lcg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001870] In another embodiment, the invention provides a method using an effective amount of IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of IFN-y containing an amount of about 10 gag to about 100 gg of drug per dose of IFN-subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001871] In another embodiment, the invention provides a method using an effective amount of IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of IFN-y containing an amount of about 10 ug to about 50 llg of drug per dose of IFN-y subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (M in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001872] In another embodiment, the invention provides a method using an effective amount of IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 90 u. g to about 100 pg of drug per dose of IFN-y subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE (M in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001873] In another embodiment, the invention provides a method using an effective amount of IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of IFN-y containing an amount of about 200 llg to about 300 llg of drug per dose of IFN-y subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001874] In another embodiment, the invention provides a method using an effective amount of IFN-and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a total weekly dosage of IFN-y containing an amount of about 30 llg to about 1, 000 gag of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEV in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001875] In another embodiment, the invention provides a method using an effective amount of IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a total weekly dosage of IFN-y containing an amount of about 100 Ag to about 300 llg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001876] In another embodiment, the invention provides a method using an effective amount of IFN-y and TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of IFN-y containing an amount of about 30 ig to about 600 llg of drug per dose of IFN-y subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, and a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001877] The anti-fibrotic effect or other therapeutic benefit of such regimens can be enhanced by co-administering to the patient a weight-based dosage of pirfenidone or a specific pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 3600 mg, or about 800 mg to about 2400 mg, or about 1000 mg to about 1800 mg, or about 1200 mg to about 1600 mg, orally qd for the desired duration of Type II interferon receptor agonist and TNF-a antagonist therapy.

[001878] In many embodiments, a Type II interferon receptor agonist and/or TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. In embodiments utilizing co-administration of pirfenidone or a specific pirfenidone analog, the duration of therapy with pirfenidone or a specific pirfenidone analog can be coincident with the duration of therapy with Type II interferon receptor agonist and/or TNF-a antagonist.

[001879] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of 50 ug Actimmune (D human IFN-ylb administered subcutaneously tiw ; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADEO/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001880] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of 100 jig Actimmune human IFN-ylb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001881] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of 25 llg Actimmune (D human IFN-lb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE&commat;/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001882] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of 200 ug Actimmune human IFN-ylb administered subcutaneously tiw; and a dosage of TNF-a antagonist selected from the group consisting of (i) 2-5 mg ENBRELO administered subcutaneously biw (ii) 3 mg REMICADE (g)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

6c. Type II interferon receptor agonist and TNF antagonist combination therapy, further comprising administering N-acetyl cysteine (NAC) to treat fibrotic disorders [001883] Any of the above-described treatment regimens for treating a fibrotic disorder can be modified to include administering an effective amount of N-acetylcysteine (NAC).

[001884] Effective dosages of NAC can range from about 100 mg-to about 1000 mg per day, or from about 100 mg to about 500 mg per day, or from about 500 mg to about 750 mg per day, or from about 750 mg to about 1000 mg per day, or from about 400 mg to about 3600 mg per day, or from about 800 mg to about 2400 mg per day, or from about 1000 mg to about 1800 mg per day, or from about 1200 mg to about 1600 mg per day.

[001885] NAC can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, three times per day, or in divided daily doses ranging from 2 to 5 times daily.

[001886] NAC can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001887] In some embodiments, NAC is administered throughout the entire course of the subject combination therapy. In other embodiments, NAC is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[001888] In some embodiments, NAC is administered at a dosage of NAC containing an amount of from about 500 mg to about 3000 mg of NAC per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration.

[001889] In some embodiments, NAC is administered at a dosage of 500 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001890] In other embodiments, NAC is administered at a dosage of 600 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001891] In other embodiments, NAC is administered at a dosage of 750 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001892] In other embodiments, NAC is administered at a dosage of 1000 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

7) Pirfenidone and TNF antagonist in combination therapy to treat fibrotic disorders [001893] In connection with each of the methods described herein, the invention provides embodiments in which the TNF-a antagonist is administered to the patient by a controlled drug delivery device. In some embodiments, the TNF-a antagonist is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the TNF-a antagonist to the patient substantially continuously or continuously by subcutaneous infusion.

[001894] In other embodiments, the TNF-a antagonist is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the TNF-a antagonist at a substantially steady state for the duration of the TNF-a antagonist therapy. Optionally, an implantable infusion pump is used to deliver the TNF-a antagonist to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the TNF-a antagonist at a substantially steady state for the duration of the TNF-a antagonist therapy.

[001895] Effective dosages of a TNF-a antagonist range from 0. 1 u. g to 40 mg per dose, e. g., from about 0. 1 ug to about 0. 5 u, g per dose, from about 0.5 llg to about 1. 0 gag per dose, from about 1. zug per dose to about 5. zug per dose, from about 5. 0 ig to about 10 µg per dose, from about 10 ug to about 20 u, g per dose, from about 20 ug per dose to about 30 ug per dose, from about 30 u. g per dose to about 40 u. g per dose, from about 40 llg per dose to about 50 ug per dose, from about 50 ug per dose to about 60 ttg per dose, from about 60 tug per dose to about 70 pg per dose, from about 70 llg to about 80 u. g per dose, from about 80 µg per dose to about 100 llg per dose, from about 100 ru to about 150 gag per dose, from about 150 wu to about 200 llg per dose, from about 200 u, g per dose to about 250 ug per dose, from about 250 Zg to about 300 ug per dose, from about 300 llg to about 400 Zg per dose, from about 400 llg to about 500 u. g per dose, from about 500 u, g to about 600 u. g per dose, from about 600 u. g to about 700 µg per dose, from about 700 jig to about 800 u, g per dose, from about 800 gag to about 900 zig per dose, from about 900 g to about 1000 wog per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001896] In some embodiments, the TNF-a antagonist is ENBREL (I etanercept. Effective dosages of etanercept range from about 0.1 u. g to about 40 mg per dose, from about 0.1 llg to about 1 u. g per dose, from about 1 lAg to about 10 µg per dose, from about 10 llg to about 100 zug per dose, from about 100 llg to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[001897] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g. , from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[001898] In some embodiments, the TNF-a antagonist is REMICADE&commat;. Effective dosages of REMICADE range from about about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2. 5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[001899] In some embodiments the TNF-a antagonist is HUMIRATM. Effective dosages of HUMIRATM range from about 0.1 llg to about 35 mg, from about 0. 1 ug to about 1 ug, from about 1 ug to about 10 u. g, from about 10 ug to about 100 u. g, from about 100 Rg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[001900] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time (e. g. , 2 years, 3 years, or longer). The TNF-a antagonist can be administered three times a day (tid), twice a day (bid), daily (qd), every other day (qod), twice per week (biw), three times per week (tiw), once per week (qw), every other week (qow), three times per month, once monthly, substantially continuously, or continuously.

[001901] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[001902] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos., 5,310, 562; 5,518, 729; 5,716, 632; and 6,090, 822.

[001903] Pirfenidone or a pirfenidone analog is administered once per month, twice per month, three times per month, once per week ; twice per week,-three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001904] In some embodiments, pirfenidone or a pirfenidone analog is administered throughout the entire course of TNF-a antagonist treatment. In other embodiments, pirfenidone or a pirfenidone analog is administered less than the entire course of TNF-a antagonist treatment, e. g. , only during the first phase of TNF-a antagonist treatment, only during the second phase of TNF-a antagonist treatment, or some other portion of the TNF-a antagonist treatment regimen.

[001905] In some embodiments, the pirfenidone or pirfenidone analog and TNF-a antagonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the pirfenidone or pirfenidone analog and the TNF-a antagonist are administered separately, e. g. , in separate formulations. In some of these embodiments, the pirfenidone or pirfenidone analog and the TNF-a antagonist are administered separately, and are administered simultaneously. In other embodiments, the pirfenidone or pirfenidone analog and the TNF-a antagonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[001906] Multiple doses of pirfenidone or pirfenidone analog and/or TNF-a antagonist can be administered, e. g. , the pirfenidone or pirfenidone analog and/or TNF-a antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001907] In some embodiments, where pirfenidone or pirfenidone analog, and TNF-a antagonist are administered in combination therapy, the two drugs are co-formulated in a single liquid formulation that is contained in a single reservoir, for use in oral delivery. Thus, the present invention provides a pharmaceutical formulation comprising a liquid formulation comprising a single dose of pirfenidone or pirfenidone analog, and a single dose of TNF-a antagonist. Thus, the present invention provides a drug reservoir or other container containing pirfenidone or pirfenidone analog, and TNF-a antagonist co-formulated in a liquid, wherein the two drugs are present in the formulation in an amount suitable for one dose each. Dosage amounts are described herein. The reservoir can be provided in any of a variety of forms, including, but not limited to, a capsule, a dropper, and the like. The invention further provides a drug delivery device comprising (e. g. , pre-loaded with) a reservoir containing a liquid formulation that comprises a single dose of pirfenidone or pirfenidone analog, and a single dose of TNF-a antagonist. Exemplary, non-limiting drug delivery devices include oral delivery devices, such as oral inhalation devices, droppers, oral syringes, and the like. Any of the dosage amounts, including synergistically effective amounts, described herein can be used in the pharmaceutical formulation, in the reservoir, or in the drug delivery device.

[001908] In other embodiments, where the pirfenidone or pirfenidone analog, and TNF-a antagonist are administered in combination therapy, each of the drugs is in a pharmaceutical formulation contained in a separate reservoir in the same drug delivery device. The invention further provides a drug delivery device that is pre-loaded with separate reservoirs, one reservoir containing a liquid formulation comprising a single dose of pirfenidone or pirfenidone analog, and a second reservoir containing a liquid formulation comprising a single dose of a TNF-a antagonist. Any of the dosage amounts, including synergistically effective amounts, described herein can be used in the pharmaceutical formulation, in the reservoir, or in the drug delivery device.

[001909] In some embodiments, in a treatment method described herein, the subject method comprises co-administering to the patient an effective amount of pirfenidone or pirfenidone analog for the duration of the TNF-a antagonist. In some embodiments, the pirfenidone or pirfenidone analog is administered to the patient orally. In some of these embodiment, the TNF-a antagonist is administered to the patient by a drug delivery device. In some embodiments, the device is used to deliver the TNF-a antagonist to the patient by substantially continuous or continuous administration. In other embodiments, the device is used to deliver the TNF-a antagonist to the patient by bolus administration tiw, biw, qod, or qd.

7a. Additional therapeutic agents for use in pirfenidone and TNF antagonist combination therapy to treat fibrotic disorders [001910] In some embodiments, a subject combination therapy comprises administering pirfenidone or a pirfenidone analog, a TNF-a antagonist, and at least a third therapeutic agent.

Suitable additional therapeutic agents include Type I interferon agonists or Type III interferon agonists, and Type II interferon agonists. In some embodiments, a subject combination therapy comprises administering (i) pirfenidone or a pirfenidone analog, (ii) a TNF-a antagonist, and (iii) a Type I interferon agonist or a Type III interferon agonist. In some embodiments, a subject combination therapy comprises administering (i) pirfenidone or a pirfenidone analog, (ii) a TNF-a antagonist, and (iii) a Type II interferon agonist. In some embodiments, a subject combination therapy comprises administering (i) pirfenidone or a pirfenidone analog, (ii) a TNF-a antagonist, (iii) a Type I interferon agonist or a Type III interferon agonist; and (iv) a Type II interferon agonist.

[001911] As used herein, the term"a Type I interferon receptor agonist"refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds to and causes signal transduction via the receptor. Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like. Type I interferon receptor agonists include an IFN-a ; an IFN- (3 ; an IFN- tau; an IFN-co ; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists.

[001912] As used herein, the term"a Type II interferon receptor agonist"refers to any naturally- occurring or non-naturally-occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like. A specific example of a Type II interferon receptor agonist is IFN- gamma (IFN-y) and variants-thereof.- [001913] As used herein, the term"a Type III interferon receptor agonist"refers to any naturally occurring or non-naturally occurring ligand of humanIL-28 receptor a ("IL-28R"), the amino acid sequence of which is described by Sheppard, et al. , infra. , that binds to and causes signal transduction via the receptor. Type III interferon agonists include an IL-28b polypeptide; and IL-28a polypeptide; and IL-29 polypeptide; antibody specific-for a Type III interferon receptor; and any other agonist of Type III interferon receptor, including non-polypeptide agonists. IL- 28A, IL-28B, and IL-29 (referred to herein collectively as"Type III interferons"or"Type III IFNs") are described in Sheppard et al. (2003) Nature 4: 63-68.

[001914] In some embodiments, the Type II interferon receptor agonist is an IFN-&gamma;. Effective dosages of IFN-y can range from about 0.5 pg/m2 to about 500 µg/m2, usually from about 1.5 pg/m2 to 200 pLg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 u. g of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously.

[001915] In specific embodiments of interest, IFN-&gamma; is administered to an individual in a unit dosage form of from about 25 llg to about 500 u. g, from about 50 llg to about 400 u. g, or from about 100 µg to about 300 u. g. In particular embodiments of interest, the dose is about 200 llg IFN-&gamma;. In many embodiments of interest, IFN-ylb is administered.

[001916] Where the dosage is 200 ug IFN-y per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 u. g IFN-y per kg body weight to about 1. 48 µg IFN-&gamma; per kg body weight.

[001917] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 ug/m2 to about 20 ug/m2. For example, an IFN-y dosage ranges from about 20 pg/m2 to about 30 µg/m2, from about 30, ug/m2 to about 40 µg/m2, from about 40 ug/m2 to about 50, ug/m2, from about 50 µg/m2 to about 60 llg/m2, from about 60 ug/m2 to about 70 llg/m2, from about 70 µg/m2 to about 80 llg/m2, from about 80 µg/m2 to about 90 µg/m2, from about 90 µg/m2 to about 100 µg/m2, from about 100 µg/m2 to about 110, ug/m2, from about 110 µg/m2 to about 120 µg/m2, from about 120 µg/m2 to about 130 ug/m2, from about 130 ug/m2 to about 140 ßg/m2, or from about 140 µg/m2 to about 150, ug/m2. In some embodiments, the dosage groups range from about 25 ug/m2 to about 100 µg/m2. In other embodiments, the dosage groups range from about 25 Mg/m2 to about 50 µg/m2.

[001918] A Type I or III interferon receptor agonist can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[001919] In some embodiments, the Type I or III interferon receptor agonist is an IFN-a.

Effective dosages of an IFN-a can range from about 1 llg to about 30 gag, from about 3 llg to about 27 u. g, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 u. g to about 180 u. g, or from about 18 u. g to about 90 u. g.

[001920] Effective dosages of Infergen&commat; consensus IFN-a include about 3 u. g, about 9 gg, about 15 u. g, about 18 u. g, or about 27 llg of drug per dose. Effective dosages of IFN-a2a and IFN- a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 sug to 180 u. g, or about 135 gag, of drug per dose.

Effective dosages of PEGylated IFN-a2b can contain an amount of about 0.5 u, g to 1.5 Fg of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 18 ug to about 90 u. g, or from about 27 Ag to about 60 u. g, or about 45 u. g, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

7b. Pirfenidone and TNF antagonist combination therapy to treat fibrotic disorders [001921] Individuals with fibrosis who are suitable for treatment according to the methods of the invention include individuals who have been clinically diagnosed with fibrosis, as well as individuals who have not yet developed clinical fibrosis but who are considered at risk of developing fibrosis.

[001922] In one aspect, the invention provides a method of treating fibrosis in a patient comprising administering to the patient an amount of pirfenidone or a pirfenidone analog and TNF-a antagonist effective to reduce fibrosis or reduce the rate of progression of fibrotic disease. Optionally, as noted above, the method of the invention provides for administering to the patient the combination of a Type I or III interferon receptor agonist, and/or a Type II interferon receptor agonist and TNF-a antagonist along with an amount of pirfenidone or a pirfenidone analog effective to reduce fibrosis or reduce the rate of progression of fibrotic disease.

[001923] In another aspect, the invention provides a method of increasing function in an organ affected by fibrosis in a patient, comprising administering to the patient an amount of pirfenidone or a pirfenidone analog, and a TNF-a antagonist effective to increase function of the affected organ.

[001924] In another aspect, the invention provides a method of reducing the incidence of a complication of cirrhosis of the liver in a patient suffering from liver fibrosis, comprising administering to the patient an amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist effective to reduce the incidence of a complication of cirrhosis of the liver.

[001925] In some embodiments, the pirfenidone or a pirfenidone analog, and TNF-a antagonist are administered in the same formulation. In other embodiments, the pirfenidone or a pirfenidone analog, and TNF-a antagonist are administered in separate formulations. When administered in separate formulations, the pirfenidone or a pirfenidone analog, and TNF-a antagonist can be administered substantially simultaneously, or can be administered within about 24 hours of one another. In many embodiments, the pirfenidone or a pirfenidone analog, and TNF-a antagonist are administered subcutaneously in multiple doses.

[001926] In many embodiments, the pirfenidone or a pirfenidone analog, and/or the TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. Dosage regimens can include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, and once bimonthly administrations.

[001927] In some embodiments, the invention provides methods using a synergistically effective amount of pirfenidone or a pirfenidone analog, and TNF-a antagonist in the treatment of fibrosis in a patient. In some embodiments, the invention provides methods using a synergistically effective amount of pirfenidone or a pirfenidone analog, and a TNF-a antagonist selected from the group consisting of ENBREL (g), REMICADE (g) and HUMIRATM, in the treatment of fibrosis in a patient. In one embodiment, the invention provides a method using a synergistically effective amount of pirfenidone, and a TNF-a antagonist selected from the group consisting of ENBRELO, REMICADEC and HUMIRATM, in the treatment of fibrosis in a patient.

[001928] In some embodiments, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEO in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and a dosage of pirfenidone or a pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight, or a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses, administered orally qd for the desired treatment duration.

[001929] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of pirfenidone or a specific pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight orally qd for the desired treatment duration; and a dosage of ENBREL (D in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001930] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of pirfenidone or a specific pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight orally qd for the desired treatment duration; and a dosage of REMICADE (g) in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001931] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a dosage of pirfenidone or a specific pirfenidone analog in the range of about 5 mg/kg of body weight to about 125 mg/kg of body weight orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001932] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of ENBRELS in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001933] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001934] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001935] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 2400 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of ENBREL (D in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001936] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 2400 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001937] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 400 mg to about 2400 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001938] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 800 mg to about 2400 mg in a single dose or two or three divided doses orally qd for the desired treatment duration ; and a dosage of ENBREL (t in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001939] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 800 mg to about 2400 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001940] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 800 mg to about 2400 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001941] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in an amount of about 800 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of ENBREL in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001942] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in an amount of about 800 mg in a single dose or two or three divided doses orally qd for the desired treatment duration ; and a dosage of REMICADE (g) in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001943] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in an amount of about 800 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001944] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1000 mg to about 1800 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of ENBREL (D in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001945] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1000 mg to about 1800 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of REMICADES in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001946] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1000 mg to about 1800 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001947] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1200 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of ENBREL (t in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001948] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1200 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration ; and a dosage of REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001949] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1200 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001950] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1200 mg to about 1600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of ENBREL (Wi in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001951] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1200 mg to about 1600 mg in a single dose or two or three divided doses orally qd for the desired-treatment duration ; and a dosage of REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001952] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1200 mg to about 1600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001953] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in an amount of about 1200 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of ENBREL (g) in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001954] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in an amount of aboutl200 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of REMICADE (D in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001955] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in an amount of about 1200 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001956] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1800 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of ENBRELO in an amount of about 25 mg of drug subcutaneously biw, for the desired treatment duration.

[001957] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1800 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of REMICADE (g in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001958] In one embodiment, the invention provides a method using an effective amount of pirfenidone or a pirfenidone analog and a TNF-a antagonist in the treatment of fibrosis in a patient, comprising administering to the patient a fixed dosage of pirfenidone or a specific pirfenidone analog in the range of about 1800 mg to about 3600 mg in a single dose or two or three divided doses orally qd for the desired treatment duration; and a dosage of HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[001959] In many embodiments, pirfenidone or a pirfenidone analog and/or a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. In embodiments utilizing co- administration of pirfenidone or a specific pirfenidone analog, the duration of therapy with pirfenidone or a specific pirfenidone analog can be coincident with the duration of therapy with TNF-a antagonist.

[001960] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of pirfenidone or pirfenidone analog in a range of from about 5 mg/kg body weight to about 125 mg/kg body weight administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADE/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001961] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of from about 400 mg to about 3600 mg pirfenidone or a pirfenidone analog administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELO administered subcutaneously biw (ii) 3 mg REMICADE (g)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001962] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of from about 400 mg to about 2400 mg pirfenidone or a pirfenidone analog administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELO administered subcutaneously biw (ii) 3 mg REMICADE (g)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001963] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of from about 800 mg to about 2400 mg pirfenidone or a pirfenidone analog administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELS administered subcutaneously biw (ii) 3 mg REMICADE (S)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001964] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a viral infection with a regimen of about 800 mg pirfenidone or a pirfenidone analog administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELO administered subcutaneously biw (ii) 3 mg REMICADE (it)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001965] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a viral infection with a regimen of from about 1000 mg to about 1800 mg pirfenidone or a pirfenidone analog administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELtE) administered subcutaneously biw (ii) 3 mg REMICADE)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001966] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of from about 1200 mg to about 3600 mg pirfenidone or a pirfenidone analog administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL (B administered subcutaneously biw (ii) 3 mg REMICADE (g)/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001967] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder with a regimen of from about 1200 mg to about 1600 mg pirfenidone or a pirfenidone analog administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL (g) administered subcutaneously biw (ii) 3 mg REMICADE&commat;/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow; for the desired duration of therapy.

[001968] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of about 1200 mg pirfenidone or a pirfenidone analog administered orally qd; a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBREL administered subcutaneously biw (ii) 3 mg REMICADEO/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow for the desired duration of therapy.

[001969] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering to an individual having a fibrotic disorder a regimen of from about 1800 mg to about 3600 mg pirfenidone or a pirfenidone analog administered orally qd; and a dosage of TNF-a antagonist selected from the group consisting of (i) 25 mg ENBRELt) administered subcutaneously biw (ii) 3 mg REMICADE&commat;/kg patient body weight administered intravenously at weeks 0,2 and 6, and every 8 weeks thereafter or (iii) 40 mg HUMIRATM subcutaneously qw or qow for the desired duration of therapy.

7c. Pirfenidone and TNF antagonist combination therapy, further comprising administering N-acetyl cysteine (NAC) to treat fibrotic disorders [001970] Any of the above-described treatment regimens for treating a fibrotic disorder can be modified to include administering an effective amount of N-acetylcysteine (NAC).

[001971] Effective dosages of NAC can range from about 100 mg to about 1000 mg per day, or from about 100 mg to about 500 mg per day, or from about 500 mg to about 750 mg per day, or from about 750 mg to about 1000 mg per day, or from about 400 mg to about 3600 mg per day, or from about 800 mg to about 2400 mg per day, or from about 1000 mg to about 1800 mg per day, or from about 1200 mg to about 1600 mg per day.

[001972] NAC can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, three times per day, or in divided daily doses ranging from 2 to 5 times daily.

[001973] NAC can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001974] In some embodiments, NAC is administered throughout the entire course of the subject combination therapy. In other embodiments, NAC is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[001975] In some embodiments, NAC is administered at a dosage of NAC containing an amount of from about 500 mg to about 3000 mg of NAC per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration.

[001976] In some embodiments, NAC is administered at a dosage of 500 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001977] In other embodiments, NAC is administered at a dosage of 600 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001978] In other embodiments, NAC is administered at a dosage of 750 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[001979] In other embodiments, NAC is administered at a dosage of 1000 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

8) Type II interferon receptor agonist and TGF-ß antagonist in combination therapy to treat fibrotic disorders [001980] In connection with each of the methods described herein, the invention provides embodiments in which the therapeutic agent, e. g., Type II interferon receptor agonist, a TUF-0 antagonist, etc. , is administered to the patient by a controlled drug delivery device. In some embodiments, the therapeutic agent, e. g. , a TGF- (3 antagonist is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient substantially continuously or continuously by subcutaneous infusion.

[001981] In other embodiments, the therapeutic agent, e. g. , a Type II interferon receptor agonist, TGF-ß antagonist, etc. , is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy.

[001982] Effective dosages of IFN-y can range from about 0. 5 µg/m2 to about 500 µg/m2, usually from about 1.5 llg/m2 to 200 µg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 ig of protein. IFN-y can be administered daily, every other day, three times a week (tiw), or substantially continuously or continuously. In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 ug to about 500 ptg, from about 50 llg to about 400 ug, or from about 100 ug to about 300 µg. In particular embodiments of interest, the dose is about 200 µg IFN-&gamma;. In many embodiments of interest, IFN-ylb is administered. In some embodiments, the IFN-y is Actimmune human IFN-&gamma;1b.

[001983] Where the dosage is 200 µg IFN-&gamma; per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4. 4 µg IFN-&gamma; per kg body weight to about 1. 48 µg IFN-&gamma; per kg body weight.

[001984] The body surface area of individuals to be treated generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-&gamma; dosage ranges from about 150 µg/m2 to about 20 Zg/m2. For example, an IFN-y dosage ranges from about 20 µg/m2 to about 30 µg/m2, from about 30 ug/m2 to about 40 llg/m2, from about 40 ug/m2 to about 50 Fg/m2, from about 50 ug/m to about 60 µg/m2, from about 60 µg/m2 to about 70 pg/m2, from about 70 Fg/m2 to about 80, ug/m2, from about 80 µg/m2 to about 90, ug/m2, from about 90 µg/m2 to about 100 µg/m2, from about 100 µg/m2 to about 110 µg/m2, from about 110 µg/m2 to about 120 ug/m2, from about 120 ug/m2 to about 130 µg/m2, from about 130 llg/m2 to about 140 µg/m2, or from about 140 ug/m2 to about 150 µg/m2. In some embodiments, the dosage groups range from about 25 µg/m2 to about 100 Zg/m2. In other embodiments, the dosage groups range from about 25 llg/m2 to about 50 µg/m2.

[001985] In many embodiments, multiple doses of an IFN-y are administered. For example, an IFN-y is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001986] In some embodiments, the IFN-is Actimmune (t human IFN-lb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 u, g, 50 u. g, 100 wu, 150 pg, or 200 ug.

[001987] In some embodiments, effective dosages of IFN-y range from about 0.5 pg/m2 to about 500 ug/m2, e. g. , from about 1.5 pg/m2 to 200 pg/m2, depending on the size of the patient. This activity is based on 106 international units (IU) per 50 llg of protein.

[001988] Where the agent is a polypeptide, polynucleotide (e. g. , a polynucleotide encoding IFN- y), it may be introduced into tissues or host cells by any number of routes, including viral infection, microinjection, or fusion of vesicles. Jet injection may also be used for intramuscular administration, as described by Furth et al. (1992), Anal Biochem 205: 365-368.

The DNA may be coated onto gold microparticles, and delivered intradermally by a particle bombardment device, or"gene gun", as described in the literature (see, for example, Tang et al.

(1992), Nature 356: 152-154), where gold microprojectiles are coated with the therapeutic DNA, then bombarded into skin cells. Of particular interest in these embodiments is use of a liver-specific promoter to drive transcription of an operably linked IFN-y coding sequence preferentially in liver cells.

[001989] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[001990] In particular embodiments of interest, IFN-y is administered as a solution suitable for subcutaneous injection. For example, IFN-y is in a formulation containing 40 mg mannitol/mL, 0. 72 mg sodium succinate/mL, 0.10 mg polysorbate 20/mL. In particular embodiments of interest, IFN-y is administered in single-dose forms of 200 wg/dose subcutaneously.

[0019911 Multiple doses of IFN-y can be administered, e. g., IFN-y can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In particular embodiments of interest, IFN-y is administered three times per week over a period of about 48 weeks.

[001992] In some embodiments, a Type II interferon receptor agonist (e. g., IFN-y) is administered throughout the entire course of TGF-ß antagonist treatment. In other embodiments, a Type II interferon receptor agonist is administered less than the entire course of TGF-P antagonist treatment, e. g. , only during the first phase of TGF- (3 antagonist treatment, only during the second phase of TGF-P antagonist treatment, or some other portion of the TGF- (3 antagonist treatment regimen.

[001993] In some embodiments, the Type II interferon receptor agonist and TGF-ß antagonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and the TGF-ß antagonist are administered separately, e. g. , in separate formulations. In some of these embodiments, the Type II interferon receptor agonist and the TGF- (3 antagonist are administered separately, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and the TGF- (3 antagonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[001994] Effective dosages of a TGF-P antagonist include a weight-based dosage in the range from about 0. 25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 pLg to about 1000 mg per day (e. g. , from about 25 pg to about 50 u. g, from about 50 ug to about 75 u. g, from about 75 llg to about 100 u, g, from about 100 ug to about 200, ut, from about 200 pg to about 500 u. g, from about 500 p, g to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day), administered orally, subcutaneously, intravenously, or intramuscularly. The dosage will depend, in part, on the specific TGF-P antagonist administered.

[001995] In some embodiments, the TGF-ß antagonist is GLEEVECTM. Suitable dosages of GLEEVECTM include, e. g. , from about 25 mg to about 1000 mg daily, e. g. , 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, or 900 mg to 1000 mg of Gleevec daily. In certain embodiments, the total daily dose is administered to a subject as two daily doses of 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, or 400 mg to 500 mg. In a particular embodiment, GLEEVECTM is administered in an amount of 400 mg GLEEVECTMorally daily. In another particular embodiment, GLEEVECTM is administered in an amount of 600 mg GLEEVECTM orally daily.

[001996] A TGF-P antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001997] Multiple doses of a TGF-ß antagonist can be administered, e. g., the TGF-ß antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[001998] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF- (3 antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of IFN-y, in a size-based dosage in the range from about 25, ug/m2 to about 100 pg/m2, or a fixed dosage of from about zig to about 200 gg, administered subcutaneously tiw for the desired treatment duration; and b) a dosage a TGF- (3 antagonist containing an amount of from about 25 gag to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[001999] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a size-based dosage of IFN-&gamma; containing an amount of from about 25 llg/m2 to about 100 ug/m2, or a fixed dosage of IFN-y containing an amount of from about 50gag to about 200 jug, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of GleevecTM containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002000] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-&gamma; containing an amount of from about 25 vag/m2 to about 100 ug/m2 IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002001] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25, ug/m2 to about 50 ug/m2 IFN-r, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of GleevecTM containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002002] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF- (3 antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about zig to about 200 llg IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of GleevecTM containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002003] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF- antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 50, ug to about 100 ug IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of GleevecTM containing an amount of 400 mg, administered orally once daily for the desired treatment. duration, to treat the fibrotic disorder.

[002004] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of about 200 u. g IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002005] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF- (3 antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 llg/m2 to about 100 Fg/m2 IFN-y, administered subcutaneously tiw for the desired treatment duration ; and b) a dosage of GleevecTM containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002006] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25, ug/m2 to about 50 ug/m2 IFN-y, administered suboutaneously tiw for the desired treatment duration; and b) a dosage of GleevecTM containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002007] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-P antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 50µg to about 200 ag IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of GleevecTM containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002008] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 50u. g to about 100 llg IFN-, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of GleevecTM containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002009] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-P antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of about 200 llg IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of GleevecTM containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

8a Combination therapy comprising administering a Type II interferon agonist, a TGF-P antagonist, and at least one additional therapeutic agent to treat fibrotic disorders [002010] Any of the above-described treatment regimens can be modified by administration of one or more additional therapeutic agents. Suitable additional therapeutic agents include, but are not limited to, pirfenidone or a pirfenidone analog, a tumor necrosis factor (TNF) antagonist, an endothelin receptor antagonist, a Type I interferon receptor agonist, and the like.

Pilzgenidone or a pirfenidone analog 8b. Combination therapy comprising administering a Type II interferon agonist, a TGF- P antagonist, and pirfenidone to treat fibrotic disorders [002011] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos., 5,310, 562; 5, 518, 729; 5,716, 632; and 6,090, 822.

[002012] Pirfenidone or a pirfenidone analog is administered once per month, twice per month, 'three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002013] Multiple doses of pirfenidone or pirfenidone analog can be administered, e. g. , the pirfenidone or pirfenidone analog can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002014] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 llg to about 500 llg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-ß antagonist containing an amount of from about 25 llg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

[002015] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF- (3 antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 llg/m2 to about 100, ug/m2, or a fixed dosage of IFN-&gamma; containing an amount of from about 50-g to about 200 u. g, administered subcutaneously tiw for the desired treatment duration ; b) a dosage of a TGF-P antagonist containing an amount of from about 25 u. g to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

[002016] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-&gamma; containing an amount of from about 25, ug/m2 to about 100 llg/m2, or a fixed dosage of IFN-&gamma; containing an amount of from about 50 llg to about 200 µg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of Gleevec containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

8c. Combination therapy comprising administering a Type II interferon agonist and a TGF-ß antagonist, further comprising administering a TNF antagonist, to treat fibrotic disorders [002017] In some embodiments, a subject therapeutic regimen further involves administering a TNF antagonist that is different from and in addition to the TGF-P antagonist in the regimen.

Effective dosages of a TNF-a antagonist range from 0. 1 u, g to 40 mg per dose, e. g. , from about 0.1 llg to about 0.5 Ag per dose, from about 0.5 llg to about 1.0 u, g per dose, from about 1.0 Zg per dose to about 5. zug per dose, from about 5. zug to about 10 llg per dose, from about 10 u. g to about 20 µg per dose, from about 20 gag per dose to about 30 llg per dose, from about 30 wu per dose to about 40 ug per dose, from about 40 llg per dose to about 50 µg per dose, from about 50 ug per dose to about 60, ut per dose, from about 60 µg per dose to about 70 llg per dose, from about 70, ut to about 80 µg per dose, from about 80 ßg per dose to about 100 µg per dose, from about 100 llg to about 150 µg per dose, from about 150 ttg to about 200 ug per dose, from about 200 µg per dose to about 250 ug per dose, from about 250 llg to about 300 llg per dose, from about 300 tug to about 400 µg per dose, from about 400 µg to about 500 llg per dose, from about 500 llg to about 600 ug per dose, from about 600 llg to about 700 wu per dose, from about 700 µg to about 800 wu per dose, from about 800 µg to about 900 ug per dose, from about 900 µg to about 1000 gag per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[002018] In some embodiments, the TNF-a antagonist is ENBREL etanercept. Effective dosages of etanercept range from about 0. 1 u. g to about 40 mg per dose, from about 0.1 µg to about 1 llg per dose, from about 1 u. g to about 10 µg per dose, from about 10 zig to about 100 llg per dose, from about 100 u, g to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[002019] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g. , from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[002020] In some embodiments, the TNF-a antagonist is REMICADE# infliximab. Effective dosages of REMICADEO range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[002021] In some embodiments the TNF-a antagonist is HUMIRATM adalimumab. Effective dosages of HUMIRATM range from about 0.1 pg to about 35 mg, from about 0. 1, ug to about 1 llg, from about 1 jug to about 10 ug, from about 10 fig to about 100 llg, from about 100 ag to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[002022] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[002023] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002024] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[002025] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-J3 antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 u, g to about 500 u. g subcutaneously tid ; bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-P antagonist containing an amount of from about 25 gag to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0. 1 ig to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002026] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 ug/m2 to about 100 pg/m2, or a fixed dosage of IFN-y containing an amount of from about 50 u. g to about 200 u. g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-ß antagonist containing an amount of from about 25 llg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 Zg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002027] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-P antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25, ug/m2 to about 100 llg/m2, or a fixed dosage of IFN-y containing an amount of from about 50gag to about 200 u. g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of GleevecTM containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEX) in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the fibrotic disorder.

[002028] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens that comprise administering a Type II interferon receptor agonist, a TGF-ß antagonist, and a TNF antagonist, where the modification involves further administering an effective amount of pirfenidone or a pirfenidone analog. Effective amounts of pirfenidone or a pirfenidone analog are discussed above.

[002029] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, iii) a TNF antagonist, and iv) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN- y containing an amount of from about 25 zg to about 500 u. g subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-P antagonist containing an amount of from about 25 Ag to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; c) a dosage of a TNF antagonist containing an amount of from about 0. 1 u, g to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly; and d) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, for the desired treatment duration, to treat the fibrotic disorder.

[002030] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-P antagonist, iii) a TNF antagonist, and iv) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 Zg/m2 to about 100 Zg/m2, or a fixed dosage of IFN-y containing an amount of from about 50 u, g to about 200 u. g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-ß antagonist containing an amount of from about 25 llg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; c) a dosage of a TNF antagonist containing an amount of from about 0.1 wu to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

[002031] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF- antagonist, iii) a TNF antagonist, and iv) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25, ug/m2 to about 100 zg/m2, or a fixed dosage of IFN-y containing an amount of from about 50gag to about 200 u, g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of GleevecTM containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELW in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and d) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

8d. Combination therapy comprising administering a Type II interferon agonist and a TGF-ß antagonist, further comprising administering an endothelin receptor antagonist, to treat fibrotic disorders [002032] In some embodiments, a subject therapeutic regimen further involves administering an endothelin receptor antagonist. Effective dosages of an endothelin receptor antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 ig to about 1000 mg per day (e. g. , from about 25 pg to about 50 ug, from about 50 pg to about 75 gag, from about 75 llg to about 100 u. g, from about 100 ug to about 200 u. g, irom about 200 u. g to about 500 gg, from about 500 llg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day).

The dosage will depend, in part, on the specific endothelin receptor antagonist administered.

An endothelin receptor antagonist is generally administered orally, subcutaneously, intravenously, or intramuscularly, although other routes of administration are also possible.

[002033] In some embodiments, the endothelin receptor antagonist is TRACLEERTM. Suitable dosages of TRACLEERTM include, e. g., from about 25 mg to about 150 mg once or twice daily, e. g. , from about 25 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 125 mg, or from about 125 mg to about 150 mg of TRACLEERTM once or twice daily. In some embodiments, TRACLEERTM is administered in an amount of 62.5 mg TRACLEERTMorally bid for 4 weeks, followed by administering TRACLEERTM in an amount of 125 mg bid orally for the desired treatment duration.

[002034] An endothelin receptor antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002035] Multiple doses of an endothelin receptor antagonist can be administered, e. g. , the endothelin receptor antagonist can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002036] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-&gamma; containing an amount of from about 25 llg to about 500 jjg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-ß antagonist containing an amount of from about 25 gag to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an endothelin receptor antagonist containing an amount of from about 25 ; j, g to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002037] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-P antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-&gamma; containing an amount of from about 25, ug/m2 to about 100 zg/m2, or a fixed dosage of IFN-y containing an amount of from about 50, ut to about 200 µg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-P antagonist containing an amount of from about 25 gag to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an endothelin receptor antagonist containing an amount of from about 25 jj. g to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002038] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-&gamma; containing an amount of from about 25, ug/m2 to about 100, ug/m2, or a fixed dosage of IFN-&gamma; containing an amount of from about 50 g to about 200 gg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of GleevecTM containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of TRACLEERTM containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

8e. Combination therapy comprising administering a Type II interferon agonist and a TGF-P antagonist, further comprising administering a Type I interferon receptor agonist, to treat fibrotic disorders [002039] In some embodiments, a subject therapeutic regimen further involves administering a Type I interferon receptor agonist. In many embodiments, the Type I interferon receptor agonist is an IFN-a. Effective dosages of an IFN-a can range from about 1 µg to about 30 µg, from about 3 llg to about 27 u. g, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 llg to about 180 it, or from about 18 gag to about 90 µg.

[002040] Effective dosages of Infergen (g) consensus IFN-a include about 3 u, g, about 9 u. g, about 15 ug, about 18 u. g, or about 27 u. g of drug per dose. Effective dosages of IFN-a2a and IFN- a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 llg to 180 u. g, or about 135 u. g, of drug per dose.

Effective dosages of PEGylated IFN-a2b can contain an amount of about 0. 5 ug to 1. 5 pug of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 10 wu to about 100 u. g, or about 18 llg to about 90 , ut, or about 27 ug to about 60 µg, or about 45 u, g, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[002041] In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered. In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered at a dosing interval of every 7 days. In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered at a dosing interval of every 8 days to every 14 days, e. g. , once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. Effective dosages of monoPEG (30 kD, linear)-ylated INFERGEN consensus IFN- a generally range from about 45 wu to about 270 u. g per dose, e. g., 60 u. g per dose, 100 llg per dose, 150 llg per dose, 200 ug per dose, etc.

[002042] In many embodiments, an IFN-a is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.

The IFN-a can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[002043] In many embodiments, multiple doses of an IFN-a are administered. For example, an IFN-a is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002044] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 gag to about 500 ng subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-ß antagonist containing an amount of from about 25 llg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) INFERGEN containing an amount of about 1 llg to about 30 pg of drug per dose of INFERGEN (g) suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 ug to about 100 u, g, or about 45 u. g to about 60 u. g, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYSW containing an amount of about 90 wu to about 360 u. g, or about 180 u. g, ofdmg per dose of PEGASYS# subcutaneously qw, qow, three times per month, or monthly (v) PEG- INTRO&commat; containing an amount of about 0.75 llg to about 3.0 llg, or about 1.0 llg to about 1.5 µg, of drug per kilogram of body weight per dose of PEG-INTRON# subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 llg to about 200 u. g, or about 150 zug, of drug per dose of mono PEG (30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder.

[002045] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 llg/m2 to about 100, ug/m2, or a fixed dosage of IFN-y containing an amount of from about 50 ug to about 200 µg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-ß antagonist containing an amount of from about 25 llg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) INFERGENO containing an amount of about 1 llg to about 30 µg of drug per dose of INFERGEN subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 Mg to about 100 µg, or about 45 llg to about 60 llg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 zig to about 360 u. g, or about 180 u. g, of drug per dose of PEGASYSO subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRONt) containing an amount of about 0. 75 gag to about 3.0 u. g, or about 1. 0 ig to about 1. 5 u. g, of drug per kilogram of body weight per dose of PEG-INTRON# subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-&alpha; containing an amount of from about 100 llg to about 200 u. g, or about 150 u, g, of drug per dose of mono PEG (30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002046] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-ß antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-&gamma; containing an amount of from about 25 Ilg/m2 to about 100 ug/m2, or a fixed dosage of IFN-&gamma; containing an amount of from about 50µg to about 200 u. g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of Gleevec containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) INFERGEN containing an amount of about 1 pg to about 30 llg of drug per dose of INFERGENW suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 u. g to about 100 u. g, or about 45 llg to about 60 llg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYSO containing an amount of about 90 u. g to about 360 wu, or about 180 gag, of drug per dose of PEGASYS (t subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 pg to about 3.0 gg, or about 1.0 llg to about 1. 5 u. g, of drug per kilogram of body weight per dose of PEG-INTRON (t suboutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear)-ylated consensus IFN-a containing an amount of from about 100 llg to about 200 llg, or about 150 u. g, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002047] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist regimen can be modified to replace the subject TGF-P antagonist regimen with a regimen of GleevecTM comprising administering a dosage of GleevecTM containing an amount of 400 mg to 800 mg, or 600 mg, of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002048] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 25 jig of drug per dose, subcutaneously three times per week for the desired treatment duration.

49] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 50, ug of drug per dose, subcutaneously three times per week for the desired treatment duration.

50] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week for the desired treatment duration.

51] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 200 vau of drug per dose, subcutaneously three times per week for the desired treatment duration.

52] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF-, B antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 50 p. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

53] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 100 , g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002054] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 200 gag of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002055] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002056] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002057] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 200 jig of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002058] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-y containing an amount of 50 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002059] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks ; and (c) administering a dosage of IFN-y containing an amount of 100 gag of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002060] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF- (3 antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-y containing an amount of 200 u, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002061] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF- (3 antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF- (3 antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-y containing an amount of 50 wog of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002062] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily ; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002063] As non-limiting examples, any of the above-described treatment methods featuring a TGF- (3 antagonist, TNF antagonist and Type II interferon receptor agonist combination-- regimen can be modified to replace the subject TGF-ß antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF- (3 antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of6QP mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage ofIFN-y containing an amount of 200 u, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002064] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist, an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF- (3 antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of therapy ; and (c) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002065] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of TracleerTM containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-y containing an amount of 100 ag of drug per dose ; subcutaneously three times per week ; for the desired treatment duration.

[002066] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of TracleerTM containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-y containing an amount of 200 u, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002067] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-y containing an amount ouf 50 gag of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002068] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF- (3 antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

69] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF- (3 antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of TracleerTM containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-y containing an amount of 200 sug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

70] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 ug of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 200 ug of drug per dose, subcutaneously three times per week ; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

71] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-P antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 ug of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 100 gag of drug per dose, subcutaneously three times per week ; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

72] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 ug of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 50 gag of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002073] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 u, g of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 50 u. g of drug per dose, subcutaneously three times per week ; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002074] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 ig of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec containing an amount of 400 mg of drug per dose, orally once daily ; for the desired treatment duration.

[002075] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF- (3 antagonist combination regimen can be modified to replace the subject IFN- a, IFN-and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 jig of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 200 jig of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002076] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to-replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 ug of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-&gamma; containing an amount of 50 gag of drug per dose, subcutaneously. three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002077] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 u. g of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002078] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-P antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF- (3 antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 ttg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 200 Fg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002079] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 9 wog of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 200 ttg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002080] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-P antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-P antagonist combination regimen with an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGENOO interferon alfacon-1 containing an amount of 9 jig of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 50 jig of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002081] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF- (3 antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGENS interferon alfacon-1 containing an amount of 9 tg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002082] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-P antagonist combination regimen with an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 9 ig of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 200 wu of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002083] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-&gamma; and TGF- (3 antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 9 u. g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-&gamma; containing an amount of 50 ig of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002084] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-P antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (D interferon alfacon-1 containing an amount of 9 ug of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 100 wu of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002085] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-P antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 15 u. g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002086] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (t interferon alfacon-1 containing an amount of 15 sug of drug per dose, subcutaneously three times per week ; (b) administering a dosage of IFN-y containing an amount of 50 tug of drug per dose, subcutaneously three times per week ; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002087] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-P antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising : (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 gag of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-&gamma; containing an amount of 100 pg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

88] As non-limiting examples, any of the above-described methods featuring an IFN-&alpha;, IFN-y and TGF-p antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 15 llg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-&gamma; containing an amount of 200 µg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

89] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 15 u, g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-&gamma; containing an amount of 50 llg of drug per dose, subcutaneously three times per week ; and (c) administering a dosage of Gleevec containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

90] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF- [3 antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 15 wu of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

91] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF- (3 antagonist combination regimen with an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 tg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 200 pg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

92] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-P antagonist combination regimen with an IFN-a, IFN-y and TGF-0 antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 gg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-&gamma; containing an amount of 100 llg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

93] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF- [3 antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 llg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-&gamma; containing an amount of 50 ug of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

94] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 u. g of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 50 µg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

95] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF- (3 antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 µg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002096] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 u, g of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevecrm containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002097] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 tug of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-&gamma; containing an amount of 50 u, g of drug per dose, subcutaneously three times per week ; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002098] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 u. g of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002099] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-P antagonist combination regimen with an IFN-a, IFN-y and TGF-P antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 llg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-&gamma; containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

00] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (I interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 200 ug of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

01] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-P antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN- and TGF- (3 antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 gag of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 50 ig of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

02] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-P antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (D interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

03] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising : (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 9 gag of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 200 µg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

04] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-&gamma; and TGF-P antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEND interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 50 u. g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

05] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF- [3 antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (t interferon alfacon-1 containing an amount of 9 ug of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-&gamma; containing an amount of 100 µg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

06] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 15 ug of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 200 gag of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

07] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGENS interferon alfacon-l containing an amount of"l 5, ug of drug per dose, subcutaneously three times per week ; (b) administering a dosage of IFN-&gamma; containing an amount of 50 llg of drug per dose, subcutaneously three times per week; and (c) administering, a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002108] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-&gamma; and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 15 llg of drug per dose, subcutaneously three times per week ; (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002109] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-&gamma; and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGENS interferon alfacon-1 containing an amount of 15 g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002110] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 15 5, ug of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 50 gag of drug per dose, subcutaneously three times per week; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002111] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TGF-ß antagonist combination regimen can be modified to replace the subject IFN- a, IFN-y and TGF-ß antagonist combination regimen with an IFN-a, IFN-y and TGF-P antagonist combination regimen comprising: (a) administering a dosage of INFERGENt) interferon alfacon-1 containing an amount of 15 u. g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 100 wu of drug per dose, subcutaneously three times per week ; and (c) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily ; for the desired treatment duration.

[002112] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 pg to 360 Jug, or 180 , g, of drug per dose, subcutaneously once weekly for the desired treatment duration.

[002113] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 0. 5 gag to 2.0 Rg, or 1. 0 llg to 1. 5 u. g, of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.

[002114] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

9) SAPK inhibitors in monotherapy and combination therapy for the treatment of fibrotic disorders [002115] In some embodiments, the present invention provides methods of treating a fibrotic disorder in an individual, comprising administering to the individual in need thereof an effective amount of a SAPK inhibitor in monotherapy or in combination therapy. In these embodiments, the method generally involves administering an effective amount of an agent that inhibits a stress-activated protein kinase (SAPK), otherwise referred to herein as"a SAPK- inhibitor, "e. g. , the agent inhibits enzymatic activity of a SAPK, where the SAPK inhibitor is other than pirfenidone or a pirfenidone analog, and where the SAPK inhibitor is other than a compound of Formula I as set forth in U. S. Patent Publication No. 20030149041.

[002116] In connection with each of the methods described herein, the invention provides embodiments in which an active agent (e. g. , a SAPK inhibitor, a Type II interferon receptor agonist, a Type I interferon receptor agonist, etc. ) is administered to the patient by a controlled drug delivery device. In some embodiments, an active agent (e. g. , a SAPK inhibitor, a Type II interferon receptor agonist, a Type I interferon receptor agonist, etc. ) is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the active agent to the patient substantially continuously or continuously by subcutaneous infusion.

[002117] In other embodiments, an active agent (e. g. , a SAPK inhibitor, a Type II interferon receptor agonist, a Type I interferon receptor agonist, etc. ) is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy.

SAPK inhibitors [002118] Effective dosages of a SAPK inhibitor range from about 5 llg to about 3000 mg, e. g., from about 5 Zg to about 10 ug, from about 10 pg to about 25 Rg, from about 25 u. g to about 50 ug, from about 50 llg to about 100 u. g, from about 100 u. g to about 250 ug, from about 250 llg to about 500 u. g, from about 500 llg to about 750 u. g, from about 750 ig to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 500 mg, from about 500 mg to about 1000 mg, from about 1000 mg to about 1500 mg, from about 1500 mg to about 2000 mg, from about 2000 mg to about 2500 mg, or from about 2500 mg to about 3000 mg.

[002119] A SAPK inhibitor can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, or in divided daily doses ranging from once daily to 5 times daily.

[002120] A SAPK inhibitor can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002121] In some embodiments, where a subject therapy is a combination therapy, a SAPK inhibitor is administered throughout the entire course of the subject combination therapy (e. g., SAPK inhibitor/Type II interferon receptor agonist combination therapy, SAPK inhibitor/Type II interferon receptor agonist/Type I interferon receptor agonist combination therapy, etc. ). In other embodiments, a SAPK inhibitor is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[002122] In some embodiments, the invention provides a method for treating a fibrotic disorder in an individual in need thereof, the method comprising administering an effective amount of a SAPK inhibitor, wherein the SAPK inhibitor is one that inhibits enzymatic activity of p38a, p38ß, and p38Y [002123] In some embodiments, the invention provides a method for treating a fibrotic disorder in an individual in need thereof, the method comprising administering an effective amount of a SAPK inhibitor, wherein the SAPK inhibitor is one that inhibits enzymatic activity of p38a, p38ß, or p38Y [002124] In some embodiments, the invention provides a method for treating a fibrotic disorder in an individual in need thereof, the method comprising administering an effective amount of a SAPK inhibitor, wherein the SAPK inhibitor is one that preferentially inhibits enzymatic activity of p38a and p38 (3 (i. e. , the agent is a stronger inhibitor of the enzymatic activity of p38a and p38ß than that of p38Y).

[002125] In some embodiments, the invention provides a method for treating a fibrotic disorder in an individual in need thereof, the method comprising administering an effective amount of a SAPK inhibitor, wherein the SAPK inhibitor is one that preferentially inhibits enzymatic activity of p38y (i. e. , the agent is a stronger inhibitor of the enzymatic activity of p38y than that of p38a and p38p).

9a. Combination therapy comprising administering a SAPK inhibitor and at least one additional anti-fibrotic agent for the treatment of fibrotic disorders [002126] Any of the above-described treatment regimens can be modified by administration of one or more additional anti-fibrotic agents. Suitable additional anti-fibrotic agents include, but are not limited to, a Type II interferon receptor agonist, a tumor necrosis factor (TNF) antagonist, a TGF- (3 antagonist, an endothelin receptor antagonist, and the like.

9b. Combination therapy comprising administering a SAPK inhibitor and a Type II interferon receptor agonist for the treatment of fibrotic disorders [002127] In some embodiments, a subject combination therapy involves modifying any of the above-described regimens by administering a Type II interferon receptor agonist, e. g., IFN-y.

Effective dosages of IFN-y can range from about 0. 5 pg/m2 to about 500 llg/m2, usually from about 1. 5 µg/m2 to 200 pg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 u, g of protein. IFN-&gamma; can be administered daily, every other day, three times a week, or substantially continuously or continuously. In specific embodiments of interest, IFN-&gamma; is administered to an individual in a unit dosage form of from about 25 ug to about 500 ag, from about 50 µg to about 400 u. g, or from about 100 ug to about 300 Zg. In particular embodiments of interest, the dose is about 200 µg IFN-&gamma;. In many embodiments of interest, IFN-ylb is administered ; In some embodiments, the IFN-y is Actimmune human IFN-ylb.

[002128] Where the dosage is 200 µg IFN-&gamma; per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 llg IFN-y per kg body weight to about 1.48 µg IFN-&gamma; per kg body weight.

[002129] The body surface area of individuals to be treated generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 µg/m2 to about 20 ug/m2. For example, an IFN-&gamma; dosage ranges from about 20, ug/m2 to about 30 , ug/m2, from about 30, ug/m2 to about 40, ug/m2, from about 40 ug/m2 to about 50 µg/m2, from about 50 µg/m2 to about 60 µg/m2, from about 60 µg/m2 to about 70 u. g/m, from about 70 , ug/m2 to about 80, ug/m2, from about 80 µg/m2 to about 90 ug/m2, from about 90 µg/m2 to about 100 µg/m2, from about 100 llg/m2to about 110 ug/m2, from about 110 µg/m2 to about 120 ug/m2, from about 120 ug/m2 to about 130 llg/m2, from about 130 µg/m2 to about 140 µg/m2, or from about 140 µg/m2 to about 150 Fg/m2. In some embodiments, the dosage groups range from about 25 µg/m2 to about 100, ug/m2. In other embodiments, the dosage groups range from about 25 µg/m2 to about 50 µg/m2.

[002130] In many embodiments, multiple doses of an IFN-y are administered. For example, an IFN-y is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002131] In some embodiments, the IFN-y is Actimmune (S) human IFN-ylb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 µg. 50 µg, 100 µg, 150 ug, or 200 µg.

[002132] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 µg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 llg to about 1000 mg per day, or about 100 sug to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of IFN-&gamma; containing an amount of from about 25 u. g to about 500 gg subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002133] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a SAPK inhibitor, in a weight-based dosage in the range from about 10 µg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 µg to about 1000 mg per day, or about 100 vag to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of Actimmune RO human IFN-ylb containing an amount of about 25 µg, 50 u, g, 100 u. g, 150 u. g, or 200 u. g, administered subcutaneously tiw, to treat the fibrotic disorder.

9c. Combination therapy comprising administering a SAPK inhibitor, further comprising administering a TNF antagonist, for the treatment of fibrotic disorders [002134] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering a TNF antagonist. Effective dosages of a TNF-a antagonist range from 0. 1, ug to 40 mg per dose, e. g. , from about 0.1 llg to about 0. 5 u. g per dose, from about 0.5 u. g to about 1. 0 gag per dose, from about 1.0 Zg per dose to about 5.0 g per dose, from about 5. 0 u. g to about 10 jug per dose, from about 10 ttg to about 20 ug per dose, from about 20 ug per dose to about 30 µg per dose, from about 30 llg per dose to about 40 u. g per dose, from about 40 ug per dose to about 50 ug per dose, from about 50, ut per dose to about 60 ug per dose, from about 60 u. g per dose to about 70 wu per dose, from about 70 llg to about 80 llg per dose, from about 80 µg per dose to about 100 llg per dose, from about 100 llg to about 150 u. g per dose, from about 150 ug to about 200 llg per dose, from about 200 ug per dose to about 250 llg per dose, from about 250 u. g to about 300 u. g per dose, from about 300 u. g to about 400 ug per dose, from about 400 u. g to about 500 pg per dose, from about 500 u. g to about 600 llg per dose, from about 600 llg to about 700 jig per dose, from about 700 u, g to about 800 gg per dose, from about 800 u, g to about 900 ug per dose, from about 900 ug to about 1000 llg per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from-about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about-40 mg per dose.

[002135] In some embodiments, the TNF-a antagonist is ENBRELW etanercept. Effective dosages of etanercept range from about 0.1 llg to about 40 mg per dose, from about 0.1 u. g to about 1 wu per dose, from about 1 llg to about 10 ug per dose, from about 10 jig to about 100 Rg per dose, from about 100 llg to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[002136] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g. , from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[002137] In some embodiments, the TNF-a antagonist is REMICADE infliximab. Effective dosages of REMICADE (g) range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2. 5 mg/kg to about 3.0 mg/kg, from about 3. 0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[002138] In some embodiments the TNF-a antagonist is HUMIRATM adalimumab. Effective dosages of HUMIRATM range from about 0. 1 ug to about 35 mg, from about 0. 1 u, g to about 1 u, g, from about 1 llg to about 10 u. g, from about 10 llg to about 100 u, g, from about 100 u. g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[002139] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[002140] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002141] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[002142] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10) J. g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 llg to about 1000 mg per day, or about 100 , ug to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration ; and b) a dosage of a TNF antagonist containing an amount of from about 0. 1 ug to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration ; to treat the fibrotic disorder.

[002143] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10, ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 wu to about-1000 mg per day, or about 100 u. g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEt in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the fibrotic disorder.

[002144] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering a SAPK inhibitor and a TNF antagonist, where the modification involves further administering an effective amount of a Type II interferon receptor agonist. Effective amounts of Type II interferon receptor agonists are discussed above.

[002145] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, ii) a TNF antagonist, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 llg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 u. g to about 1000 mg per day, or about 100 u, g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day ; or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; b) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration ; and c) a dosage of Actimmune#human IFN-&gamma;1b containing an amount of about 25 u. g, 50 u. g, 100 ug, 150 llgj or 200 gag, administered subcutaneously tiw, to treat the fibrotic disorder.

[002146] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering a SAPK inhibitor and a TNF antagonist, where the modification involves further administering an effective amount of a TGF-ß antagonist. Effective amounts of TGF-P antagonists are discussed below.

[002147] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering a SAPK inhibitor and a TNF antagonist, where the modification involves further administering an effective amount of an endothelin receptor antagonist. Effective amounts of endothelin receptor antagonists are discussed below.

9d. Combination therapy comprising administering a SAPK inhibitor, further comprising administering a TGF-ß antagonist, for the treatment of fibrotic disorders [002148] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering a TGF-P antagonist. Effective amounts of a TGF- P antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 pg to about 1000 mg per day (e. g., from about 25 u. g to about 50 u. g, from about 50 ßg to about 75 u. g, from about 75 ug to about 100 wog, from about 100 Zg to about 200 u. g, from about 200 Zg to about 500 µg, from about 500 u. g to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day), administered orally, subcutaneously, intravenously, or intramuscularly. The dosage will depend, in part, on the specific TGF-ß antagonist administered.

[002149] In some embodiments, the TGF-ß antagonist is GLEEVECTM. Suitable dosages of GLEEVECTM include, e. g., from about 25 mg to about 1000 mg daily, e. g. , 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, or 900 mg to 1000 mg of Gleevec daily. In certain embodiments, the total daily dose is administered to a subject as two daily doses of 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, or 400 mg to 500 mg. In a particular embodiment, GLEEVECTM is administered in an amount of 400 mg GLEEVECTM orally daily.-In another particular embodiment, GLEEVECTM is administered in an amount of 600 mg GLEEVECTM orally daily.

[002150] A TGF-ß antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002151] Multiple doses of a TGF-ß antagonist can be administered, e. g. , the TGF-ß antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002152] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor and ii) a TGF- (3 antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 llg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 u, g to about 1000 mg per day, or about 100 llg to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of a TGF-ß antagonist containing an amount of from about 25 jug to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002153] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor and ii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 pg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 ig to about 1000 mg per day, or about 100 u. g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of GLEEVECTM containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002154] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering a SAPK inhibitor and a TGF-P antagonist, where the modification involves further administering an effective amount of a Type II interferon receptor agonist. Effective amounts of Type II interferon receptor agonists are discussed above.

[002155] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering a SAPK inhibitor and a TGF-ß antagonist, where the modification involves further administering an effective amount of an endothelin receptor antagonist. Effective amounts of endothelin receptor antagonists are discussed below.

9e. Combination therapy comprising administering a SAPK inhibitor, further comprising administering an endothelin receptor antagonist, for the treatment of fibrotic disorders [002156] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering an endothelin receptor antagonist. Effective dosages of an endothelin receptor antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 Zg to about 1000 mg per day (e. g. , from about 25 pg to about 50 tug, from about 50 llg to about 75 u. g, from about 75 u. g to about 100 wog, from about 100 wu to about 200 ug, from about 200 u. g to about 500, ut, from about 500 u. g to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day). The dosage will depend, in part, on the specific endothelin receptor antagonist administered. An endothelin receptor antagonist is generally administered orally, subcutaneously, intravenously, or intramuscularly, although other routes of administration are also possible.

[002157] In some embodiments, the endothelin receptor antagonist is TRACLEERTM. Suitable dosages of TRACLEERTM include, e. g. , from about 25 mg to about 150 mg once or twice daily, e. g. , from about 25 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to-about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 125 mg, or from about 125 mg to about 150 mg of TRACLEERTM once or twice daily. In some embodiments, TRACLEERTM is administered in an amount of 62.5 mg TRACLEERTM orally bid for 4 weeks, followed by administering TRACLEERTM in an amount of 125 mg bid orally for the desired treatment duration.

[002158] An endothelin receptor antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002159] Multiple doses of an endothelin receptor antagonist can be administered, e. g. , the endothelin receptor antagonist can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002160] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 , ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 ug to about 1000 mg per day, or about 100 llg to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 ug to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration ; to treat the fibrotic disorder.

[002161] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 u. g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 u, g to about 1000 mg per day, or about 100 llg to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of TRACLEERTM containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[002162] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering a SAPK inhibitor and an endothelin receptor antagonist, where the modification involves further administering an effective amount of a Type II interferon receptor agonist. Effective amounts of Type II interferon receptor agonists are discussed above.

9f. Combination therapy comprising administering a SAPK inhibitor, further comprising administering a Type II interferon receptor agonist and a Type I interferon receptor agonist, for the treatment of fibrotic disorders [002163] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In many embodiments, the Type II interferon receptor agonist is IFN-y and the Type I interferon receptor agonist is an IFN-a.

[002164] Effective dosages of IFN-y are described above.

[002165] Effective dosages of an IFN-a can range from about 1 pLg to about 30 u. g, from about 3 u. g to about 27 u. g, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 llg to about 180 u. g, or from about 18 u. g to about 90 u. g. Effective dosages of Infergen consensus IFN-a include about 3 u. g, about 9 u, g, about 15 ug, about 18 u, g, or about 27 ug of drug per dose. Effective dosages of IFN-a2a and IFN-a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 u. g to 180 gag, or about 135 u. g, of drug per dose. Effective dosages of PEGylated IFN-a2b can contain an amount of about 0. 5 gag to 1. 5 gag of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 10 wu to about 100 u. g, or about 18 Rg to about 90 ; ig, or about 27 gag to about 60 ug, or about 45, ug, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[002166] In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered. In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered at a dosing interval of every 7 days. In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered at a dosing interval of every 8 days to every 14 days, e. g. , once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. Effective dosages of monoPEG (30 kD, linear)-ylated INFERGEN consensus IFN- a generally range from about 45 gag to about 270 p. g per dose, e. g., 60 gag per dose, 100 tg per dose, 150 gg per dose, 200 llg per dose, etc.

[002167] In many embodiments, an IFN-a is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.

The IFN-a can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[002168] In many embodiments, multiple doses of an IFN-a are administered. For example, an IFN-a is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002169] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a SAPK inhibitor, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 wu to about 500 u, g subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration ; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 Rg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 µg to about 1000 mg per day, or about 100 llg to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration ; and c) a dosage of an IFN-a selected from (i) INFERGEN containing an amount of about 1 u. g to about 30 wu of drug per dose of INFERGEN (g) suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 zu to about 100 µg, or about 45 llg to about 60, ug, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 u. g to about 360 ttg, or about 180 u. g, of drug per dose of PEGASYS (g) subcutaneously qw, qow, three times per month, or monthly (v) PEG- INTRON containing an amount of about 0. 75 ug to about 3.0 u. g, or about 1.0 u. g to about 1.5 µg, of drug per kilogram of body weight per dose of PEG-INTRON subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 ug to about 200 u. g, or about 150 u, g, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder.

[002170] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a SAPK inhibitor, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-&gamma; containing an amount of from about 25 llg/m2 to about 100) ng/m, or a fixed dosage of IFN-&gamma; containing an amount of from about 50 gag to about 200 tug, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10, ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 gag to about 1000 mg per day, or about 100 llg to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) INFERGEN containing an amount of about 1 Zg to about 30 zug of drug per dose ofINFERGEN (R) subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 ug to about 100 gg, or about 45 u. g to about 60 , ug, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 zug to about 360 gag, or about 180 u. g, of drug per dose of PEGASYS (» subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 llg to about 3. 0 u, g, or about 1.0 zg to about 1.5 ug, of drug per kilogram of body weight per dose of PEG-INTRON (» suboutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 tug to about 200 wog, or about 150 u. g, of drug per dose of mono PEG (30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002171] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 25 ug of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002172] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-containing an amount of 50 llg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002173] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002174] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-comprising administering a dosage of IFN-&gamma; containing an amount of 200 µg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002175] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist regimen can be modified to replace the subject TGF-ß antagonist regimen with a regimen of Gleevec comprising administering a dosage of Gleevec containing an amount of 400 mg to 800 mg, or 600 mg, of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002176] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist regimen can be modified to replace the subject endothelin receptor antagonist regimen with an endothelin receptor antagonist regimen comprising administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; for the desired treatment duration.

[002177] As non-limiting examples, any of the above-described treatment methods featuring a TNF antagonist regimen can be modified to replace the subject TNF antagonist regimen with a TNF antagonist regimen comprising administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[002178] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF- (3 antagonist and Type II interferon receptor agonist combination regimen with a TGF- (3 antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002179] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-&gamma; containing an amount of 100 u. g of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002180] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-&gamma; containing an amount of 200 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002181] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-&gamma; containing an amount of 50 fug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002182] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002183] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily ; and (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002184] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 62.5 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002185] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 62.5 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 100 , g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002186] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising : (a) administering a dosage of TRACLEERTM containing an amount of 62.5 mg of drug per dose, orally twice daily ; and (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002187] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 50 J. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002188] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002189] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising : (a) administering a dosage of TRACLEERTM containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 200 ptg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002190] As non-limiting examples, any of the above-described treatment methods featuring a TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TNF antagonist and Type II interferon receptor agonist combination regimen with a TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks ; and (b) administering a dosage of IFN-containing an amount of 50 u. g of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002191] As non-limiting examples, any of the above-described treatment methods featuring a TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TNF antagonist and Type II interferon receptor agonist combination regimen with a TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

92] As non-limiting examples, any of the above-described treatment methods featuring a TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TNF antagonist and Type II interferon receptor agonist combination regimen with a TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks ; and (b) administering a dosage of IFN-y containing an amount of 200 u, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

93] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist and a TNF antagonist combination regimen can be modified to replace the subject TGF-P antagonist and TNF antagonist combination regimen with a TGF-ß antagonist and TNF antagonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks ; for the desired treatment duration.

94] As non-limiting examples, any of the above-described treatment methods featuring a TGF- (3 antagonist and a TNF antagonist combination regimen can be modified to replace the subject TGF-P antagonist and TNF antagonist combination regimen with a TGF-P antagonist and TNF antagonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[002195] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and TNF antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TNF antagonist combination regimen with an endothelin receptor antagonist and TNF antagonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 62.5 mg of drug per dose, orally twice daily; and (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[002196] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and TNF antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TNF antagonist combination regimen with an endothelin receptor antagonist and TNF antagonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[002197] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and a TGF-P antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TGF-P antagonist combination regimen with an endothelin receptor antagonist and TGF- (3 antagonist combination regimen comprising: (a) administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day; and (b) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002198] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and a TGF-P antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TGF-P antagonist combination regimen with an endothelin receptor antagonist and TGF-P antagonist combination regimen comprising: (a) administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day; and (b) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002199] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and a TGF-ß antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TGF-ß antagonist combination regimen with an endothelin receptor antagonist and TGF- (3 antagonist combination regimen comprising: (a) administering a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day; and (b) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002200] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and a TGF-P antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TGF-P antagonist combination regimen with an endothelin receptor antagonist and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day; and (b) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002201] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 00, ug of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-&gamma; containing an amount of 200 yg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002202] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 u. g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 00, ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002203] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN- combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 ug of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 sug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002204] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 llg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002205] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 , g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002206] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 Rg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 ug of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002207] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 zig of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002208] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 u. g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of l 00 lug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002209] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 ug of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002210] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN (ít) interferon alfacon-l containing an amount of 9 pg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002211] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN# interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002212] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-l containing an amount of 9 llg of drug per dose, subcutaneously three times per week ; and (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002213] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGENS interferon alfacon-1 containing an amount of 9, ug of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 200 Zg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002214] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN (D interferon alfacon-l containing an amount of 9 pg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 50 gag of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002215] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN (t interferon alfacon-l containing an amount of 9 gag of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002216] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGENOO interferon alfacon-1 containing an amount of 15 tug of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002217] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-l containing an amount of 15 u. g ofdmg per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 50 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002218] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-&gamma; regimen comprising: (a) administering a dosage of INFERGEN (S interferon alfacon-l containing an amount of 15 u. g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 100 00 ßg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002219] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-l containing an amount of 15 llg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 200, ut of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002220] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN (I interferon alfacon-1 containing an amount of 15 u, g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 50 Rg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002221] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-l containing an amount of 15 u. g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002222] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 Rg to 360 u, g, or 180 u, g, of drug per dose, subcutaneously once weekly for the desired treatment duration.

[002223] As non-limiting examples, any'of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 0.5 ig to 2.0 u. g, or 1.0 llg to 1. 5 pLg, of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.

[002224] As non-limiting examples, any of the above-described methods that includes an endothelin receptor antagonist regimen can be modified to replace the subject endothelin receptor antagonist regimen with a regimen of endothelin receptor antagonist comprising administering a dosage of TracleerTM containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of the desired treatment duration.

[002225] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a comprising administering an amount of monoPEG (30 kD, linear) -ylated consensus IFN-a once weekly or once every 8 days can be modified to administer the amount of monoPEG (30 kD, linear) -ylated consensus IFN-a once every 10 days for the desired treatment duration.

[002226] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK inhibitor regimen comprising administering a dosage of 0. 01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002227] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002228] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002229] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002230] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

9g. Combination therapy comprising administering a SAPK inhibitor, further comprising administering N-acetyle cysteine, for the treatment of fibrotic disorders [002231] Any of the above-described treatment regimens for treating a fibrotic disorder can be modified to include administering an effective amount of N-acetylcysteine (NAC).

[002232] Effective dosages of NAC can range from about 100 mg to about 1000 mg per day, or from about 100 mg to about 500 mg per day, or from about 500 mg to about 750 mg per day, or from about 750 mg to about 1000 mg per day, or from about 400 mg to about 3600 mg per day, or from about 800 mg to about 2400 mg per day, or from about 1000 mg to about 1800 mg per day, or from about 1200 mg to about 1600 mg per day.

[002233] NAC can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, three times per day, or in divided daily doses ranging from 2 to 5 times daily.

[002234] NAC can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002235] In some embodiments, NAC is administered throughout the entire course of the subject combination therapy. In other embodiments, NAC is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[002236] In some embodiments, NAC is administered at a dosage of NAC containing an amount of from about 500 mg to about 3000 mg of NAC per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration.

[002237] In some embodiments, NAC is administered at a dosage of 500 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002238] In other embodiments, NAC is administered at a dosage of 600 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002239] In other embodiments, NAC is administered at a dosage of 750 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002240] In other embodiments, NAC is administered at a dosage of 1000 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

10) N-acetyl cysteine and SAPK inhibitor in combination therapy for treating fibrotic disorders [002241] In connection with each of the methods described herein, the invention provides embodiments in which an active agent (e. g. , a SAPK inhibitor, a Type II interferon receptor agonist, a Type I interferon receptor agonist, etc. ) is administered to the patient by a controlled drug delivery device. In some embodiments, an active agent (e. g. , a SAPK inhibitor, a Type II interferon receptor agonist, a Type I interferon receptor agonist, etc. ) is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the active agent to the patient substantially continuously or continuously by subcutaneous infusion.

[002242] In other embodiments, an active agent (e. g. , a SAPK inhibitor, a Type II interferon receptor agonist, a Type I interferon receptor agonist, etc. ) is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy.

N-acetylcysteine (NAC) [002243] Effective dosages of NAC can range from about 100 mg to about 1000 mg per day, or from about 100 mg to about 500 mg per day, or from about 500 mg to about 750 mg per day, or from about 750 mg to about 1000 mg per day, or from about 400 mg to about 3600 mg per day, or from about 800 mg to about 2400 mg per day, or from about 1000 mg to about 1800 mg per day, or from about 1200 mg to about 1600 mg per day.

[002244] NAC can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, three times per day, or in divided daily doses ranging from 2 to 5 times daily.

[002245] NAC can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002246] In some embodiments, NAC is administered throughout the entire course of the subject combination therapy (e. g. , NAC/SAPK inhibitor combination therapy, NAC/SAPK inhibitor/Type II interferon receptor agonist combination therapy, NAC/SAPK inhibitor/Type II interferon receptor agonist/Type I interferon receptor agonist combination therapy, etc. ). In other embodiments, NAC is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[002247] In some embodiments, NAC is administered at a dosage of 500 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002248] In other embodiments, NAC is administered at a dosage of 600 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002249] In other embodiments, NAC is administered at a dosage of 750 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002250] In other embodiments, NAC is administered at a dosage of 1000 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

SAPK inhibitors [002251] Effective dosages of a SAPK inhibitor range from about 5 ug to about 3000 mg, e. g., from about 5 u. g to about 10 gag, from about 10 u, g to about 25 u. g, from about 25 u, g to about 50 , ut, from about 50 llg to about 100 u. g, from about 100 llg to about 250 u, g, from about 250 tug to about 500 u. g, from about 500 llg to about 750 ug, from about 750 ig to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 500 mg, from about 500 mg to about 1000 mg, from about 1000 mg to about 1500 mg, from about 1500 mg to about 2000 mg, from about 2000 mg to about 2500 mg, or from about 2500 mg to about 3000 mg.

[002252] In some embodiments, the SAPK inhibitor is pirfenidone or a pirfenidone analog.

Effective dosages of pirfenidone or a pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos. , 5,310, 562; 5,518, 729; 5,716, 632; and 6,090, 822.

[002253] A SAPK inhibitor (e. g. , pirfenidone or a pirfenidone analog) can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, or in divided daily doses ranging from 2 to 5 times daily.

[002254] A SAPK inhibitor (e. g. , pirfenidone or a pirfenidone analog) can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002255] In some embodiments, a SAPK inhibitor (e. g. , pirfenidone or'a pirfenidone analog) is administered throughout the entire course of the subject combination therapy (e. g., NAC/SAPK inhibitor combination therapy, NAC/SAPK inhibitor/Type II interferon receptor agonist combination therapy, NAC/SAPK inhibitor/Type II interferon receptor agonist/Type I interferon receptor agonist combination therapy, etc. ). In other embodiments, a SAPK inhibitor (e. g. , pirfenidone or a pirfenidone analog) is administered less than the entire course of the combination therapy, e. g., only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[002256] In some embodiments, the invention provides a method for treating a fibrotic disorder in an individual in need thereof, the method comprising administering an effective amount of a SAPK inhibitor, wherein the SAPK inhibitor is one that inhibits enzymatic activity of p38a, p38 (3, and p38y.

[002257] In some embodiments, the invention provides a method for treating a fibrotic disorder in an individual in need thereof, the method comprising-administering an effective amount of a SAPK inhibitor, wherein the SAPK inhibitor is one that inhibits enzymatic activity of p38a, p38ß, or p38Y.

[002258] In some embodiments, the invention provides a method for treating a fibrotic disorder in an individual in need thereof, the method comprising administering an effective amount of a SAPK inhibitor, wherein the SAPK inhibitor is one that preferentially inhibits enzymatic activity of p38a and p38ß (i. e. , the agent is a stronger inhibitor of the enzymatic activity of p38a and p38(3 than that of p38y).

[002259] In some embodiments, the invention provides a method for treating a fibrotic disorder in an individual in need thereof, the method comprising administering an effective amount of a SAPK inhibitor, wherein the SAPK inhibitor is one that preferentially inhibits enzymatic activity of p38y (i. e. , the agent is a stronger inhibitor of the enzymatic activity of p38y than that of p38a andp38ß).

[002260] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002261] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 400 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002262] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 800 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002263] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1000 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002264] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1200 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002265] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1600 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002266] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1800 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002267] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 2400 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002268] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 2800 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002269] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 3200 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002270] In other embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 3600 mg orally per day, optionally in two or more divided doses per day, for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

10a. Combination therapy comprising administering NAC, a SAPK inhibitor and at least one additional anti-fibrotic agent for treating fibrotic disorders [002271] Any of the above-described treatment regimens can be modified by administration of one or more additional anti-fibrotic agents. Suitable additional anti-fibrotic agents include, but are not limited to, a Type II interferon receptor agonist, a tumor necrosis factor (TNF) antagonist, a TGF-ß antagonist, an endothelin receptor antagonist, and the like. lOb. Combination therapy comprising administering NAC and a SAPK inhibitor, further comprising administering a Type II interferon receptor agonists for treating fibrotic disorders [002272] In some embodiments, a subject combination therapy involves modifying any of the above-described regimens by administering a Type II interferon receptor agonist, e. g., IFN-y.

Effective dosages of IFN-y can range from about 0. 5 pg/m2 to about 500 µg/m2, usually from about 1.5 llg/m2 to 200 llg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 llg of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously. In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 llg to about 500 u. g, from about 50 u. g to about 400 u. g, or from about 100 llg to about 300 u, g. In particular embodiments of interest, the dose is about 200 wg IFN-y. In many embodiments of interest, IFN-ylb is administered. In some embodiments, the IFN-y is Actimmune (íg) human IFN-ylb.

[002273] Where the dosage is 200 µg IFN-&gamma; per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4. 4 µg IFN-&gamma; per kg body weight to about 1. 48 ug IFN-per kg body weight.

[002274] The body surface area of individuals to be treated generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 ug/m2 to about 20 µg/m2. For example, an IFN-y dosage ranges from about 20, ug/m2 to about 30 µg/m2, from about 30 µg/m2 to about 40 µg/m2, from about 40 µg/m2 to about 50, ug/m2, from about 50 Fg/m2 to about 60 Fg/m2, from about 60 llg/m2 to about 70 µg/m2, from about 70 zg/m2 to about 80 pg/m2, from about 80 µg/m2 to about 90 µg/m2, from about 90 ug/m2 to about 100 µg/m2, from about 100 µg/m2 to about 110 µg/m2, from about 110 ug/m2 to about 120, ug/m2, from about 120 µg/m2 to about 130 µg/m2, from about 130 µg/m2 to about 140 , ug/m2, or from about 140 llg/m2 to about 150, ug/m2. In some embodiments, the dosage groups range from about 25 wg/m2 to about 100 llg/m2. In other embodiments, the dosage groups range from about 25 llg/m2 to about 50 ßg/m2.

[002275] In many embodiments, multiple doses of an IFN-y are administered. For example, an IFN-y is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per. week, every other day (qod), daily (qd),. substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002276] In some embodiments, the IFN-y is Actimmune&commat; human IFN-y Ib, and is administered subcutaneously tiw in a dosage containing an amount of about 25 u. g, 50 u. g, 100 ug, 150 ug, or 200 ug.

[002277] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a SAPK inhibitor, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration ; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 ug to about 1000 mg per day, or about 100 ug to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration ; and c) a dosage of IFN-y containing an amount of from about 25 ug to about 500 ug subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002278] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a SAPK inhibitor, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration ; b) a SAPK inhibitor, in a weight-based dosage in the range from about 10 µg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 Fg to about 1000 mg per day, or about 100 pg to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of Actimmune human IFN-ylb containing an amount of about 25 µg, 50 µg, 100 µg, 150 ug, or 200 zg, administered subcutaneously tiw, to treat the fibrotic disorder. lOc. Combination therapy comprising administering NAC and a SAPK inhibitor, further comprising administering a TNF antagonist for treating fibrotic disorders [002279] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering a TNF antagonist. Effective dosages of a TNF-a antagonist range from 0. 1 ug to 40 mg per dose, e. g. , from about 0.1 llg to about 0.5 Rg per dose, from about 0.5 pg to about 1. 0 ug per dose, from about 1.0 Ag per dose to about 5. 0, ug per dose, from about 5.0 wu to about 10 llg per dose, from about 10 pg to about 20 pg per dose, from about 20 llg per dose to about 30 ug per dose, from about 30 ug per dose to about 40 ug per dose, from about 40 pg per dose to about 50 llg per dose, from about 50 ug per dose to about 60 ug per dose, from about 60 ug per dose to about 70 pLg per dose, from about 70 ug to about 80 llg per dose, from about 80 ßg per dose to about 100 llg per dose, from about 100 llg to about 150 µg per dose, from about 150 ug to about 200 ug per dose, from about 200 pLg per dose to about 250 µg per dose, from about 250 ug to about 300 ug per dose, from about 300 ug to about 400 llg per dose, from about 400 ug to about 500 wu per dose, from about 500 ug to about 600 ug per dose, from about 600 yg to about 700 ug per dose, from about 700 pg to about 800 lug per dose, from about 800 wu to about 900 pLg per dose, from about 900 ug to about 1000 ug per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[002280] In some embodiments, the TNF-a antagonist is ENBREL etanercept. Effective dosages of etanercept range from about 0. 1 µg to about 40 mg per dose, from about 0. 1, ug to about 1 pg per dose, from about 1, ug to about 10 ug per dose, from about 10 ug to about 100 pg per dose, from about 100 ug to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[002281] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g. , from about 0.1 mg/kg body weight to about 0. 5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7. 5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[002282] In some embodiments, the TNF-a antagonist is REMICADE infliximab. Effective dosages of REMICADE (g) range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[002283] In some embodiments the TNF-a antagonist is HUMIRATM adalimumab. Effective dosages of HUMIRATM range from about 0. 1 llg to about 35 mg, from about 0.1 ag to about 1 , ut, from about 1 u. g to about 10 u. g, from about 10 ug to about 100 wu, from about 100 ug to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[002284] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[002285] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002286] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[002287] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a SAPK inhibitor, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 u. g to about 1000 mg per day, or about 100 u. g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 u. g to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002288] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a SAPK inhibitor, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 u. g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 llg to about 1000 mg per day, or about 100 u, g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMIC-ADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMERA in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the fibrotic disorder.

[002289] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering NAC, a SAPK inhibitor and a TNF antagonist, where the modification involves further administering an effective amount of a Type II interferon receptor agonist. Effective amounts of Type II interferon receptor agonists are discussed above.

[002290] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a SAPK inhibitor, iii) a TNF antagonist, and iv) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10, ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 ag to about 1000 mg per day, or about 100 u, g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; c) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBRELO in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration ; and d) a dosage of Actimmune (g) human IFN-lb containing an amount of about 25 pug, 50 llg, 100 yg, 150 pg, or 200 ug, administered subcutaneously tiw, to treat the fibrotic disorder.

[002291] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering NAC, a SAPK inhibitor and a TNF antagonist, where the modification involves further administering an effective amount of a TGF-ß antagonist. Effective amounts of TGF-ß antagonists are discussed below.

[002292] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering NAC, a SAPK inhibitor and a TNF antagonist, where the modification involves further administering an effective amount of an endothelin receptor antagonist. Effective amounts of endothelin receptor antagonists are discussed below.

10d. Combination therapy comprising administering NAC and a SAPK inhibitor, further comprising administering a TGF-P antagonist for treating fibrotic disorders [002293] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering a TGF-ß antagonist. Effective amounts of a TGF- p antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 llg to about 1000 mg per day (e. g., from about 25 ug to about 50. ug, from about 50 llg to about 75 ug, from about 75 ug to about 100 ug, from about 100 ug to about 200 ug, irom about 200 ug to about 500 ug, from about 500 ug to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day), administered orally, subcutaneously, intravenously, or intramuscularly. The dosage will depend, in part, on the specific TGF-ß antagonist administered.

[002294] In some embodiments, the TGF- (3 antagonist is GLEEVECTM. Suitable dosages of GLEEVECTM include, e. g. , from about 25 mg to about 1000 mg daily, e. g. , 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, or 900 mg to 1000 mg of GleevecTM daily. In certain embodiments, the total daily dose is administered to a subject as two daily doses of 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, or 400 mg to 500 mg. In a particular embodiment, GLEEVECTM is administered in an amount of 400 mg GLEEVECTM orally daily. In another particular embodiment, GLEEVECTMis administered in an amount of 600 mg GLEEVECTM orally daily.

[002295] A TGF- (3 antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002296] Multiple doses of a TGF-ß antagonist can be administered, e. g. , the TGF- (3 antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from- about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002297] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a SAPK inhibitor and iii) a TGF- (3 antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 zg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 llg to about 1000 mg per day, or about 100 ug to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration ; and c) a dosage of a TGF-P antagonist containing an amount of from about 25 wu to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002298] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, i) a SAPK inhibitor and iii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration ; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 llg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 jig to about 1000 mg per day, or about 100 Ag to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration ; and c) a dosage of GLEEVECTM containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002299] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering NAC, a SAPK inhibitor and a TGF-ß antagonist, where the modification involves further administering an effective amount of a Type II interferon receptor agonist. Effective amounts of Type II interferon receptor agonists are discussed above.

[002300] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering NAC, a SAPK inhibitor and a TGF-P antagonist, where the modification involves further administering an effective amount of an endothelin receptor antagonist. Effective amounts of endothelin receptor antagonists are discussed below : 10e. Combination therapy comprising administering NAC and a SAPK inhibitor, further comprising administering an endothelin receptor antagonist for treating fibrotic disorders [002301] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering an endothelin receptor antagonist. Effective dosages of an endothelin receptor antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 gag to about 1000 mg per day (e. g. , from about 25 llg to about 50 u. g, from about 50 llg to about 75 , ut, from about 75 u. g to about 100 u. g, from about 100 u. g to about 200 gag, from about 200 pLg to about 500 u. g, from about 500 u, g to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day). The dosage will depend, in part, on the specific endothelin receptor antagonist administered. An endothelin receptor antagonist is generally administered orally, subcutaneously, intravenously, or intramuscularly, although other routes of administration are also possible.

[002302] In some embodiments, the endothelin receptor antagonist is TRACLEERTM. Suitable dosages of TRACLEERTM include, e. g., from about 25 mg to about 150 mg once or twice daily, e. g. , from about 25 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 125 mg, or from about 125 mg to about 150 mg of TRACLEERTM once or twice daily. In some embodiments, TRACLEERTM is administered in an amount of 62.5 mg TRACLEER TM orally bid for 4 weeks, followed by administering TRACLEERTM in an amount of 125 mg bid orally for the remainder of the desired treatment duration.

[002303] An endothelin receptor antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from 2 to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002304] Multiple doses of an endothelin receptor antagonist can be administered, e. g. , the endothelin receptor antagonist can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002305] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a SAPK inhibitor and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10, ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 ug to about 1000 mg per day, or about 100 gag to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration ; and c) a dosage of an endothelin receptor antagonist containing an amount of from about 25 p, g to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to, treat the fibrotic disorder.

[002306] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a SAPK inhibitor and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 Mg to about 1000 mg per day, or about 100 ig to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of TRACLEERTM containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[002307] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens featuring administering NAC, a SAPK inhibitor and an endothelin receptor antagonist, where the modification involves further administering an effective amount of a Type II interferon receptor agonist. Effective amounts of Type II interferon receptor agonists are discussed above. lOf. Combination therapy comprising administering NAC and a SAPK inhibitor, further comprising administering a Type II interferon receptor agonist and a Type I interferon receptor agonist, for treating fibrotic disorders [002308] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering a Type II interferon receptor agonist and a Type I interferon receptor agonist. In many embodiments, the Type II interferon receptor agonist is IFN-y and the Type I interferon receptor agonist is an IFN-a.

[002309] Effective dosages of IFN-are described above.

[002310] Effective dosages of an IFN-a can range from about 1 zg to about 30 u. g, from about 3 llg to about 27 ug, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 llg to about 180 u. g, or from about 18 u, g to about 90 u. g. Effective dosages of Infergen consensus IFN-a include about 3 ug, about 9 u. g, about 15 u. g, about 18 u. g, or about 27 ug of drug per dose. Effective dosages of IFN-a2a and IFN-a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 llg to 180 u. g, or about 135 u. g, of drug per dose. Effective dosages of PEGylated IFN-a2b can contain an amount of about 0. 5 u, g to 1.5 u, g of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 10 ug to about 100 u, g, or about 18 u. g to about 90 u. g, or about 27 llg to about 60 u. g, or about 45 u. g, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[002311] In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered. In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered at a dosing interval of every 7 days. In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered at a dosing interval of every 8 days to every 14 days, e. g. , once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. Effective dosages of monoPEG (30 kD, linear)-ylated INFERGEN consensus IFN- a generally range from about 45 gag to about 270 u, g per dose, e. g., 60 gag per dose, 100 Ag per dose, 150 ug per dose, 200 Fg per dose, etc.

[002312] In many embodiments, an IFN-a is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.

The IFN-a can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[002313] In many embodiments, multiple doses of an IFN-a are administered. For example, an IFN-a is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002314] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a Type II interferon receptor agonist, iii) a SAPK inhibitor, and iv) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; b) a dosage of IFN-y containing an amount of from about 25 u, g to about 500 u. g subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; c) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 ug/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 llg to about 1000 mg per day, or about 100 llg to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration ; and d) a dosage of an IFN-a selected from (i) INFERGEN containing an amount of about 1 pg to about 30 u, g of drug per dose of INFERGEN (D suboutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 u. g to about 100 u. g, or about 45 vug to about 60 ug, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 u, g to about 360 u, g, or about 180 u. g, of drug per dose of PEGASYS (I subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 llg to about 3. 0 wu, or about 1. 0 ug to about 1. 5 ug, of drug per kilogram of body weight per dose of PEG-INTRONS subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 u. g to about 200 u. g, or about 150 u, g, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder.

[002315] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) NAC, ii) a Type II interferon receptor agonist, iii) a SAPK inhibitor, and iv) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; b) a size-based dosage of IFN-y containing an amount of from about 25 llg/m2 to about 100 ug/m2, or a fixed dosage of IFN-containing an amount of from about 50 jig to about 200 wog, administered subcutaneously tiw for the desired treatment duration; c) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 yg/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 llg to about 1000 mg per day, or about 100 ug to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and d) a dosage of an IFN-a selected from (i) INFERGEN containing an amount of about 1 gag to about 30 pg of drug per dose of INFERGEN subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 llg to about 100 u. g, or about 45. ug to about 60 llg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 u, g to about 360 u. g, or about 180 gg, of drug per dose of PEGASYSO subcutaneously qw, qow, three times per month, or monthly (v) PEG- INTRONt) containing an amount of about 0.75 llg to about 3. 0 u, g, or about 1.0 pg to about 1.5 lug, ouf drug per kilogram of body weight per dose of PEG-INTRON (g) suboutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 gag to about 200 u, g, or about 150 gg, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002316] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-Y-comprising administering a dosage of IFN-y containing an amount of 25 ug of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002317] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-&gamma; comprising administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002318] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-comprising administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002319] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-comprising administering a dosage of IFN-y containing an amount of 200 gag of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002320] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist regimen can be modified to replace the subject TGF-P antagonist regimen with a regimen of GleevecTM comprising administering a dosage of GleevecTM containing an amount of 400 mg to 800 mg, or 600 mg, of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002321] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist regimen can be modified to replace the subject endothelin receptor antagonist regimen with an endothelin receptor antagonist regimen comprising administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of therapy ; for the desired treatment duration.

[002322] As non-limiting examples, any of the above-described treatment methods featuring a TNF antagonist regimen can be modified to replace the subject TNF antagonist regimen with a TNF antagonist regimen comprising administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[002323] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF- (3 antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002324] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF- (3 antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-&gamma; containing an amount of 100 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002325] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-&gamma; containing an amount of 200 jj. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002326] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 50 gag of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002327] As non-limiting examples, any of the above-described treatment methods featuring a TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-P antagonist and Type II interferon receptor agonist combination regimen with a TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 100) J. g of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002328] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-ß antagonist and Type II interferon receptor agonist combination regimen with a TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-y containing an amount of 200 u, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002329] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 62.5 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 50 pg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002330] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 62.5 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002331] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 62.5 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-containing an amount of 200 gag of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002332] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 50 pig of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002333] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002334] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002335] As non-limiting examples, any of the above-described treatment methods featuring a TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TNF antagonist and Type II interferon receptor agonist combination regimen with a TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (b) administering a dosage of IFN-containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002336] As non-limiting examples, any of the above-described treatment methods featuring a TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TNF antagonist and Type II interferon receptor agonist combination regimen with a TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (b) administering a dosage of IFN-y containing an amount of 100 u, g of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002337] As non-limiting examples, any of the above-described treatment methods featuring a TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TNF antagonist and Type II interferon receptor agonist combination regimen with a TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002338] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and a TNF antagonist combination regimen can be modified to replace the subject TGF- (3 antagonist and TNF antagonist combination regimen with a TGF-P antagonist and TNF antagonist combination regimen comprising: (a) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks ; for the desired treatment duration.

[002339] As non-limiting examples, any of the above-described treatment methods featuring a TGF-ß antagonist and a TNF antagonist combination regimen can be modified to replace the subject TGF- (3 antagonist and TNF antagonist combination regimen with a TGF-p antagonist and TNF antagonist combination regimen comprising: (a) administering a dosage of Gleevec containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of a TNF antagonist selected from the group of (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[002340] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and TNF antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TNF antagonist combination regimen with an endothelin receptor antagonist and TNF antagonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 62.5 mg of drug per dose, orally twice daily; and (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[002341] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and TNF antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TNF antagonist combination regimen with an endothelin receptor antagonist and TNF antagonist combination regimen comprising: (a) administering a dosage of TRACLEERTM containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[002342] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and a TGF-P antagonist-combination regimen can be modified to replace the subject endothelin receptor antagonist and TGF-ß antagonist combination regimen with an endothelin receptor antagonist and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day; and (b) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002343] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and a TGF-P antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TGF-P antagonist combination regimen with an endothelin receptor antagonist and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day; and (b) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002344] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and a TGF-ß antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TGF-P antagonist combination regimen with an endothelin receptor antagonist and TGF-ß antagonist combination regimen comprising: (a) administering a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day; and (b) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[002345] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and a TGF- (3 antagonist combination regimen can be modified to replace the subject endothelin receptor antagonist and TGF-ß antagonist combination regimen with an endothelin receptor antagonist and TGF- (3 antagonist combination regimen comprising: (a) administering a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day; and (b) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[002346] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 u. g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 u. g ofdmg per dose, subcutaneously three times per week; for the desired treatment duration.

[002347] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 fig of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002348] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 u, g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002349] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 u. g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002350] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 llg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002351] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 ug of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 Uug of drug-per dose, subcutaneously three times per week; for the desired treatment duration.

[002352] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 gag of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 u, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002353] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 Zg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 ßg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002354] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 gag of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 gag of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002355] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 Ag of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 200 ig of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002356] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN (B interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously three times per week ; and (b) administering a dosage of IFN-y containing an amount of 50 pg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002357] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002358] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 9 u. g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002359] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage ofINFERGEN (R) interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount ouf 50 lug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002360] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGENO interferon alfacon-1 containing an amount of 9 gag of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002361] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 Uug of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002362] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGENS interferon alfacon-1 containing an amount of 15 u. g of drug per dose, subcutaneously three times per week ; and (b) administering a dosage of IFN-y containing an amount of 50 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002363] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN (D interferon alfacon-1 containing an amount of 15 u. g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 100 u, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002364] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 ug of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002365] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGENS interferon alfacon-1 containing an amount of 15 gag of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 50 wu of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002366] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGENt) interferon alfacon-1 containing an amount of 15 pg of drug per dose, subcutaneously once daily ; and (b) administering a dosage of IFN-y containing an amount of 100 Itg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002367] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 wu to 360 u. g, or 180 u. g, of drug per dose, subcutaneously once weekly for the desired treatment duration.

[002368] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 0.5 pg to 2. 0 u. g, or 1. 0 ug to 1. 5 u. g, of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.

[002369] As non-limiting examples, any of the-above-described methods that includes an endothelin receptor antagonist regimen can be modified to replace the subject endothelin receptor antagonist regimen with a regimen of endothelin receptor antagonist comprising administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleerz containing an amount of 125 mg of drug orally twice per day for the remainder of the desired treatment duration.

[002370] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a comprising administering an amount of monoPEG (30 kD, linear) -ylated consensus IFN-a once weekly or once every 8 days can be modified to administer the amount of monoPEG (30 kD, linear) -ylated consensus IFN-a once every 10 days for the desired treatment duration.

[002371] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK inhibitor regimen comprising administering a dosage of 0. 01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

72] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK inhibitor regimen comprising administering a dosage of 0. 1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

73] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

74] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

75] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 5 mg to 125 mg of pirfenidone or pirfenidone analog per kilogram of body weight orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

76] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 400 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

77] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 800 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

78] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 1200 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002379] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 1600 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002380] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 1800 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002381] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 2400 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002382] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 2800 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002383] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 3200 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002384] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a pirfenidone or pirfenidone analog regimen comprising administering a dosage of 3600 mg of pirfenidone or pirfenidone analog orally per day, optionally in two or more divided doses per day, for the desired treatment duration with the SAPK inhibitor compound.

[002385] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 500 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002386] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 750 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002387] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 1000 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002388] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 1200 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002389] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 1500 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002390] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 1800 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002391] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 2000 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002392] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 2500 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002393] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 3000 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002394] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

11) N-acetyl cystine and Type II interferon receptor-agonist in combination therapy for treating fibrotic disorders [002395] In connection with each of the methods described herein, the invention provides embodiments in which the therapeutic agent, e. g., Type II interferon receptor agonist, TNF antagonist, etc. , is administered to the patient by a controlled drug delivery device. In some embodiments, the therapeutic agent, e. g. , a therapeutic agent is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient substantially continuously or continuously by subcutaneous infusion.

[002396] In other embodiments, the therapeutic agent, e. g. , a Type II interferon receptor agonist, TNF antagonist, etc. , is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy.

[002397] In some embodiments, the Type II interferon receptor agonist is an IFN-y. Effective dosages of IFN-y can range from about 0.5 ßg/m2 to about 500 llg/m2, usually from about 1.5 pg/m2 to 200, ug/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 u, g of protein. IFN-y can be administered daily, every other day, three times a week (tiw), or substantially continuously or continuously. In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 llg to about 500 u. g, from about 50 zg to about 400 u, g, or from about 100 llg to about 300 u. g. In particular embodiments of interest, the dose is about 200 llg IFN-Y. In many embodiments of interest, IFN-ylb is administered. In some embodiments, the IFN-y is Actimmune (g) human IFN-lb.

[002398] Where the dosage is 200 µg IFN-&gamma; per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4. 4 ug IFN-y per kg body weight to about 1.48 µg IFN-&gamma; per kg body weight.

[002399] The body surface area of individuals to be treated generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 Ag/m2 to about 20 µg/m2. For example, an IFN-y dosage ranges from about 20 llg/m2 to about 30 , ug/m2, from about 30 llg/m2 to about 40 µg/m2, from about 40 llg/m2 to about 50 µg/m2, from about 50 µg/m2 to about 60 µg/m2, from about 60 pg/m2 to about 70 llg/m2, from about 70 pg/m2 to about 80 µg/m2, from about 80 µg/m2 to about 90 llg/m2, from about 90 Zg/m2 to about 100 ug/m2, from about 100 ßg/m2 to about 110 yg/m2, from about 110 µg/m2 to about 120 ug/m2, from about 120 µg/m2 to about 130 ug/m, from about 130 ug/m2 to about 140 Fg/m2, or from about 140 µg/m2 to about 150 µg/m2. In some embodiments, the dosage groups range from about 25 µg/m2 to about 100 pg/m2. In other embodiments, the dosage groups range from about 25 µg/m2 to about 50 µg/m2.

[002400] In many embodiments, multiple doses of an IFN-y are administered. For example, an IFN-y is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002401] In some embodiments, the IFN-y is ActimmuneV human IFN-&gamma;1b, and is administered subcutaneously tiw in a dosage containing an amount of about 25 u. g, 50 u. g, 100 ug, 150 u, g, or 200 µg.

[002402] In some embodiments, effective dosages of IFN-y range from about 0. 5 µg/m2 to about 500 µg/m2, e. g. , from about 1.5 µg/m2 to 200 µg/m2, depending on the size of the patient. This activity is based on 106 international units (IU) per 50 llg of protein.

[002403] Where the agent is a polypeptide, polynucleotide (e. g. , a polynucleotide encoding IFN- y), it may be introduced into tissues or host cells by any number of routes, including viral infection, microinjection, or fusion of vesicles. Jet injection may also be used for intramuscular administration, as described by Furth et al. (1992), Anal Biochem 205: 365-368.

The DNA may be coated onto gold microparticles, and delivered intradermally by a particle bombardment device, or"gene gun"as described in the literature (see, for example, Tang et al.

(1992), Nature 356: 152-154), where gold microprojectiles are coated with the therapeutic- DNA, then bombarded into skin cells. Of particular interest in these embodiments is use of a liver-specific promoter to drive transcription of an operably linked IFN-y coding sequence preferentially in liver cells.

[002404] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[002405] In particular embodiments of interest, IFN-y is administered as a solution suitable for subcutaneous injection. For example, IFN-y is in a formulation containing 40 mg mannitol/mL, 0.72 mg sodium succinate/mL, 0.10 mg polysorbate 20/mL. In particular embodiments of interest, IFN-y is administered in single-dose forms of 200, ug/dose subcutaneously.

[002406] Multiple doses of IFN-y can be administered, e. g., IFN-y can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In particular embodiments of interest, IFN-y is administered three times per week over a period of about 48 weeks.

[002407] In some embodiments, a Type II interferon receptor agonist (e. g., IFN-y) is administered throughout the entire course of NAC treatment. In other embodiments, a Type II interferon receptor agonist is administered less than the entire course of NAC treatment, e. g., only during the first phase of NAC treatment, only during the second phase of NAC treatment, or some other portion of the NAC treatment regimen.

[002408] In some embodiments, the Type II interferon receptor agonist and the NAC are administered in the same formulation, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and NAC are administered separately, e. g. , in separate formulations. In some of these embodiments, the Type II interferon receptor agonist and NAC are administered separately, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and NAC are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30seconds to about 60seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[002409] Effective dosages of NAC can range from about 100 mg to about 1000 mg per day, or from about 100 mg to about 500 mg per day, or from about 500 mg to about 750 mg per day, or from about 750 mg to about 1000 mg per day, or from about 400 mg to about 3600 mg per day, or from about 800 mg to about 2400 mg per day, or from about 1000 mg to about 1800 mg per day, or from about 1200 mg to about 1600 mg per day.

[002410] NAC can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice daily, three times per day, or in divided daily doses ranging from 2 to 5 times daily.

[002411] NAC can be administered at any frequency, and over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002412] In some embodiments, NAC is administered throughout the entire course of the subject combination therapy (e. g., NAC/SAPK inhibitor combination therapy, NAC/SAPK inhibitor/Type II interferon receptor agonist combination therapy, NAC/SAPK inhibitor/Type II interferon receptor agonist/Type I interferon receptor agonist combination therapy, etc. ). In other embodiments, NAC is administered less than the entire course of the combination therapy, e. g. , only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.

[002413] In some embodiments, NAC is administered at a dosage of 500 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002414] In other embodiments, NAC is administered at a dosage of 600 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002415] In other embodiments, NAC is administered at a dosage of 750 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002416] In other embodiments, NAC is administered at a dosage of 1000 mg of drug per dose orally once daily, twice daily or three times daily, for the desired treatment duration.

[002417] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y, in a size-based dosage in the range from about 25 pg/m2 to about 100 g/m2, or a fixed dosage of from about 50ig to about 200 ug, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002418] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 , ug/m2 to about 100 llg/m2 IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002419] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 pLg/m2 to about 50 Fg/m2 IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002420] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 50tig to about 200 ug IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002421] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 50pLg to about 100 g IFN-y, administered subcutaneously tiw for the desired treatment duration ; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder.

[002422] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) NAC in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of about 200 llg IFN-y, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration, to treat the fibrotic disorder. lla. Combination therapy comprising administering a Type II interferon agonist, NAC, and at least one additional therapeutic agent for treating fibrotic disorders [002423] Any of the above-described treatment regimens can be modified by administration of one or more additional therapeutic agents. Suitable additional therapeutic agents include, but are not limited to, pirfenidone or a pirfenidone analog, a tumor necrosis factor (TNF) antagonist, a TGF-P antagonist, an endothelin receptor antagonist, a Type I interferon receptor agonist, and the like. lib. Combination therapy comprising administering a Type II interferon agonist and NAC, further comprising administering pirfenidone or a pirfenidone analog for treating fibrotic disorders [002424] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U. S. Pat. Nos., 5,310, 562; 5,518, 729; 5,716, 632; and 6,090, 822 : [002425] Pirfenidone or a pirfenidone analog is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four. months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002426] Multiple doses of pirfenidone or pirfenidone analog can be administered, e. g. , the pirfenidone or pirfenidone analog can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002427] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 ug to about 500 u. g subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

[002428] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-&gamma; containing an amount of from about 25 ug/m2 to about 100 llg/m2, or a fixed dosage of IFN-containing an amount of from about 50 µg to about 200 u. g, administered subcutaneously tiw for the desired treatment duration ; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

11c. Combination therapy comprising administering a Type II interferon agonist and NAC, further comprising administering a TNF antagonist, for treating fibrotic disorders [002429] In some embodiments, a subject therapeutic regimen further involves administering a TNF antagonist. Effective amounts of a TNF-a antagonist range from 0.1 llg to 40 mg per dose, e. g. , from about 0.1 u, g to about 0.5 llg per dose, from about 0.5 llg to about 1. zug per dose, from about 1.0 gg per dose to about 5. 0 µg per dose, from about 5. 0 gag to about 10 jig per dose, from about 10 u. g to about 20 ßg per dose, from about 20 tug per dose to about 30 u. g per dose, from about 30 gag per dose to about 40 ug per dose, from about 40 gag per dose to about 50 pg per dose, from about 50 µg per dose to about 60 u, g per dose, from about 60 u, g per dose to about 70 µg per dose, from about 70 µg to about 80 zug per dose, from about 80 Rg per dose to about 100 u, g per dose, from about 100 ug to about 150 u. g per dose, from about 150 gag to about 200 llg per dose, from about 200 pg per dose to about 250 µg per dose, from about 250 Rg to about 300 Uug per dose, from about 300 llg to about 400 llg per dose, from about 400 , ug to about 500 u. g per dose, from about 500 llg to about 600 gag per dose, from about 600 llg to about 700 pug per dose, from about 700 llg to about 800 µg per dose, from about 800 ug to about 900 wu per dose, from about 900 zug to about 1000 Itg per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[002430] In some embodiments, the TNF-a antagonist is ENBREL etanercept. Effective amounts of etanercept range from about 0. 1 u. g to about 40 mg per dose, from about 0. 1, ug to about 1 llg per dose, from about 1 llg to about 10 u. g per dose, from about 10 u, g to about 100 llg per dose, from about 100 Rg to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35-mg per dose, or from about 35 mg to about 40 mg per dose.

[002431] In some embodiments, effective amounts of a TGF-&alpha; antagonist are expressed as mg/kg body weight. In these embodiments, effective amounts of a TGF-&alpha; antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e. g. , from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[002432] In some embodiments, the TNF-a antagonist is REMICADE infliximab. Effective amounts of REMICADE) range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[002433] In some embodiments the TNF-a antagonist is HUMIRATM adalimumab. Effective amounts of HUMIRATM range from about 0.1 ig to about 35 mg, from about 0.1 llg to about 1 ug, from about 1 ig to about 10 u. g, from about 10 ig to about 100 u. g, from about 100 u, g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[002434] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[002435] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002436] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[002437] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of IFN-containing an amount of from about 25 llg to about 500 llg subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration ; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 u. g to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002438] In some, embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 ug/m2 to about 100, ug/m2, or a fixed dosage of IFN-y containing an amount of from about 50 wu to about 200 gag, administered subcutaneously tiw for the desired treatment duration; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 ug to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002439] In some embodiments, the invention provides a combination. therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 llg/m2 to about 100 sug/m2, or a fixed dosage of IFN-containing an amount of from about 50pg to about 200 gag, administered subcutaneously tiw for the desired treatment duration; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; and c) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADEO in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the fibrotic disorder.

[002440] In some embodiments, the invention provides a combination therapy method involving modification of any of the above-described treatment regimens that comprise administering a Type II interferon receptor agonist, NAC, and a TNF antagonist, where the modification involves further administering an effective amount of pirfenidone or a pirfenidone analog.

Effective amounts of pirfenidone or a pirfenidone analog are discussed above.

11d. Combination therapy comprising administering a Type 11 interferon agonist and NAC, further comprising administering a TGF-P antagonist, for treating fibrotic disorders [002441] In some embodiments, a subject therapeutic regimen further involves administering a TGF-p antagonist. Effective amounts of a TGF-P antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 ug to about 1000 mg per day (e. g., from about 25 ug to about 50 u. g, from about 50 p. g to about 75 ug, from about 75, ug to about 100 u. g, from about 100 llg to about 200 jig, from about 200 llg to about 500 p. g, from about 500 pg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day), administered orally, subcutaneously, intravenously ; or intramuscularly. The dosage will depend, in part, on the specific TGF-P antagonist administered.

[002442] In some embodiments, the TGF-ß antagonist is GLEEVECTM. Suitable dosages of GLEEVECTMinclude, e. g. , from about 25 mg to about 1000 mg daily, e. g. , 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, or 900 mg to 1000 mg of Gleevec daily. In certain embodiments, the total daily dose is administered to a subject as two daily doses of 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, or 400 mg to 500 mg. In a particular embodiment, GLEEVECTM is administered in an amount of 400 mg GLEEVECTM orally daily. In another particular embodiment, GLEEVECTM is administered in an amount of 600 mg GLEEVECTM orally daily.

[002443] A TGF-P antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002444] Multiple doses of a TGF-ß antagonist can be administered, e. g. , the TGF-P antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002445] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) a TGF-ß antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of IFN-y containing an amount of from about 25 gag to about 500 pg suboutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; and c) a dosage of a TGF-ß antagonist containing an amount of from about 25 llg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[002446] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) a TGF-P antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of IFN-y containing an amount of from about 25 u. g to about 500 llg subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; and c) a dosage of GLEEVECTM containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[002447] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) a TGF- (3 antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a size-based dosage of IFN-containing an amount of from about 25 pg/m2 to about 100, ug/m2, or a fixed dosage of IFN-y containing an amount of from about 50 wog to about 200 u. g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; and c) a dosage of GLEEVECTM containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder. lie. Combination therapy comprising administering a Type II interferon agonist and NAC, further comprising administering a Type I interferon receptor agonist, for treating fibrotic disorders [002448] In some embodiments, a subject therapeutic regimen further involves administering a Type I interferon receptor agonist. In many embodiments, the Type I interferon receptor agonist is an IFN-a. Effective dosages of an IFN-a can range from about 1 ug to about 30 Rg, from about 3 ug to about 27 u. g, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 u. g to about 180 u. g, or from about 18 llg to about 90 µg.

[002449] Effective dosages of Infergen (g) consensus IFN-a include about 3 µg, about 9 µg, about 15 jug, about 18 gag, or about 27 zg of drug per dose. Effective dosages of IFN-&alpha;2a and IFN- a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 Fg to 360 u. g, or about 180 u. g, of drug per dose.

Effective dosages of PEGylated IFN-a2b can contain an amount of about 0.5 llg to 3.0 u. g, or about 1. zug to 1. 5 u. g, of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 10 wu to about 100 u. g, or about 40 Uug to about 80 u. g, or about 50 wu to about 70 u. g, or about 60 Rg, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[002450] In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-&alpha; is administered. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-a is administered at a dosing interval of every 7 days. In some embodiments, monoPEG (30 kD, linear) -ylated consensus IFN-a is administered at a dosing interval of every 8 days to every 14 days, e. g. , once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. Effective amounts of monoPEG (30 kD, linear)-ylated INFERGEN consensus IFN- a generally range from about 45 fig to about 270 µg per dose, e. g. , 60 gag per dose, 100 u. g per dose, 150 u. g per dose, 200 ug per dose, etc.

[002451] In many embodiments, an IFN-a is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.

The IFN-a can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[002452] In many embodiments, multiple doses of an IFN-a are administered. For example, an IFN-a is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[002453] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 llg to about 500 llg suboutaneously qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration ; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration ; and c) a dosage of an IFN-a selected from (i) INFERGENS containing an amount of about 1 ug to about 30 ug of drug per dose of INFERGEN subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 llg to about 100 u. g, or about 40 u. g to about 80 llg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 llg to about 360 u. g, or about 180 u, g, of drug per dose of PEGASYS (g) suboutaneously qw, qow, three times per month, or monthly (v) PEG-lNTRON (t containing an amount of about 0.75 u, g to about 3.0 gg, or about 1. zug to about 1.5 u, g, of drug per kilogram of body weight per dose-of PEG-INTRONOO subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear) -ylated consensus IFN-a containing an amount of from about 100 fig to about 200 u, g, or about 150 u. g, of drug per dose of mono PEG (30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder.

[002454] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) NAC, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-containing an amount of from about 25 llg/m2 to about 100 llg/m2, or a fixed dosage of IFN-y containing an amount of from about 50 jig to about 200 u. g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day, for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) INFERGENX containing an amount of about 1 llg to about 30 ug of drug per dose of INFERGEN (g) subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 wu to about 100 u, g, or about 40 u. g to about 80 , g, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 wu to about 360 u. g, or about 180 wog, of drug per dose of PEGASYS9 subcutaneously qw, qow, three times per month, or monthly (v) PEU-INTRO containing an amount of about 0.75 Fg to about 3.0 u, g, or about 1.0 llg to about 1. 5 wu, of drug per kilogram of body weight per dose of PEG- INTRON subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG (30 kD, linear)-ylated consensus IFN-a containing an amount of from about 100 llg to about 200 u, g, or about 150 u. g, of drug per dose of mono PEG (30 kD, linear) -ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder.

[002455] As non-limiting examples, in any of the above-described treatment methods featuring an endothelin receptor antagonist regimen the endothelin receptor antagonist regimen can be replaced with a regimen of TRACLEERTM comprising administering a dosage of TRACLEERTM containing an amount of 25 mg to 500 mg, or an amount of 125 mg to 250 mg, of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002456] As non-limiting examples, in any of the above-described treatment methods the subject Type II interferon receptor agonist regimen can be replaced with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 25 llg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002457] As non-limiting examples, in any of the above-described treatment methods the subject Type II interferon receptor agonist regimen can be replaced with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 50 ug of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002458] As non-limiting examples, in any of the above-described treatment methods the subject Type II interferon receptor agonist regimen can be replaced with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002459] As non-limiting examples, in any of the above-described treatment methods the subject Type II interferon receptor agonist regimen can be replaced with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 200 zg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[002460] As non-limiting examples, in any of the above-described treatment methods the subject NAC and Type II interferon receptor agonist combination regimen can be replaced with a NAC and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; and (b) administering a dosage of IFN-y containing an amount of 50 llg of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002461] As non-limiting examples, in any of the above-described treatment methods the subject NAC and Type II interferon receptor agonist combination regimen can be replaced with a NAC and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day ; and (b) administering a dosage of IFN-y containing an amount of 100 jig of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002462] As non-limiting examples, in any of the above-described treatment methods the subject NAC and Type II interferon receptor agonist combination regimen can be replaced with a NAC and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day ; and (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002463] As non-limiting examples, any of the above-described treatment methods featuring a NAC, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TNF antagonist and Type II interferon receptor agonist combination regimen with a NAC, TNF antagonist and Type II-interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-y containing an amount of 50 u. g of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002464] As non-limiting examples, any of the above-described treatment methods featuring a NAC, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TNF antagonist and Type II interferon receptor agonist combination regimen with a NAC, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day ; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-containing an amount of 100 ig of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002465] As non-limiting examples, any of the above-described treatment methods featuring a NAC, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TNF antagonist and Type II interferon receptor agonist combination regimen with a NAC, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of a TNF antagonist selected from the group of : (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0,2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-y containing an amount of 200 ßg of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002466] As non-limiting examples, any of the above-described treatment methods featuring a NAC, a TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TGF- (3 antagonist and Type II interferon receptor agonist combination regimen with a NAC, TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-y containing an amount of 50 p, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002467] As non-limiting examples, any of the above-described treatment methods featuring a NAC, TGF- (3 antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TGF-ß antagonist and Type II interferon receptor agonist combination regimen with a NAC, TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily ; and (c) administering a dosage of IFN-y containing an amount of 100 wu of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002468] As non-limiting examples, any of the above-described treatment methods featuring a NAC, TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TGF-P antagonist and Type II interferon receptor agonist combination regimen with a NAC, TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day ; (b) administering a dosage of GleevecTM containing an amount of 400 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002469] As non-limiting examples, any of the above-described treatment methods featuring a NAC, TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TGF-P antagonist and Type II interferon receptor agonist combination regimen with a NAC, TGF-P antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-y containing an amount ouf 50 lug of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002470] As non-limiting examples, any of the above-described treatment methods featuring a NAC, TGF-P antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TGF-P antagonist and Type II interferon receptor agonist combination regimen with a NAC, TGF- (3 antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-containing an amount of 100 llg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002471] As non-limiting examples, any of the above-described treatment methods featuring a NAC, TGF-ß antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, TGF- (3 antagonist and Type II interferon receptor agonist combination regimen with a NAC, TGF-ß antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of GleevecTM containing an amount of 600 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-containing an amount of 200 fig of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002472] As non-limiting examples, any of the above-described treatment methods featuring a NAC, an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of Tracleer containing an amount of 62.5 mg of drug per dose, orally twice daily; and (c) administering a dosage of IFN-y containing an amount of 50 yg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002473] As non-limiting examples, any of the above-described treatment methods featuring a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of Tracleer containing an amount of 62.5 mg of drug per dose, orally twice daily; and (c) administering a dosage of IFN-y containing an amount of 100 fig of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002474] As non-limiting examples, any of the above-described treatment methods featuring a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of Tracleer containing an amount of 62.5 mg of drug per dose, orally twice daily; and (c) administering a dosage of IFN-y containing an amount of 200 Ag of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002475] As non-limiting examples, any of the above-described treatment methods featuring a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination-... regimen can be modified to replace the subject NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of Tracleer containing an amount of 125 mg of drug per dose, orally twice daily; and (c) administering a dosage of IFN-y containing an amount of50u. g of drug per dose, subcutaneously three times per week ; for the desired treatment duration.

[002476] As non-limiting examples, any of the above-described treatment methods featuring a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of Tracleer containing an amount of 125 mg of drug per dose, orally twice daily ; and (c) administering a dosage of IFN-y containing an amount of 100 ig of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002477] As non-limiting examples, any of the above-described treatment methods featuring a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a NAC, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; (b) administering a dosage of Tracleer containing an amount of 125 mg of drug per dose, orally twice daily; and (c) administering a dosage of IFN-y containing an amount of 200 u, g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[002478] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 wu of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 200 ug of drug per dose, subcutaneously three times per week ; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002479] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 100 llg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week ; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002480] As non-limiting examples ; any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 llg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 50 wu of drug per dose, subcutaneously thgee times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002481] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 Rg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 50 u. g of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002482] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 llg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week ; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day ; for the desired treatment duration.

[002483] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 150 llg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 200 u. g of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002484] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 llg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 50 llg of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002485] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 ug of drug per dose, subcutaneously once weekly or once every 8 days ; (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002486] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear) -ylated consensus IFN-a containing an amount of 200 llg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002487] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 9 ug of drug per dose, subcutaneously three times per week ; (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002488] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN (» interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 50 Fg of drug per dose, subcutaneously three times per week ; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002489] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN (» interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously three times per week ; (b) administering a dosage of IFN-y containing an amount of 100 u. g of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day ; for the desired treatment duration.

[002490] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 9 Zg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 200 wu of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002491] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN (Sfl interferon alfacon-1 containing an amount of 9 g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 50 jig of drug per dose, subcutaneously three times per week ; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002492] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN (g interferon alfacon-1 containing an amount of 9 llg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 100 llg of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002493] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN (g) interferon alfacon-1 containing an amount of 15 u, g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 200 llg of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002494] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage ofINFERGEN (R) interferon alfacon-1 containing an amount of 15 wu of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 50 u. g of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

95] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN (D interferon alfacon-1 containing an amount of 15 llg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 100 ug of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

96] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGENS interferon alfacon-1 containing an amount of 15 ug of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 200 Ag of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

97] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGEN O interferon alfacon-1 containing an amount of 15 ug of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 50 pg of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

98] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and NAC combination regimen can be modified to replace the subject IFN-a, IFN-y and NAC combination regimen with an IFN-a, IFN-y and NAC combination regimen comprising: (a) administering a dosage of INFERGENO interferon alfacon-1 containing an amount of 15 ug of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 100 gg of drug per dose, subcutaneously three times per week; and (c) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; for the desired treatment duration.

[002499] As non-limiting examples, any of the above-described methods featuring an IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen can be modified to replace the subject IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen with an IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen comprising: (a) administering a dosage of IFN-y containing an amount of 50 llg of drug per dose, subcutaneously three times per week; (b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; and (c) a dosage of pirfenidone or a pirfenidone analog containing a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, optionally in two or more divided doses per day; for the desired treatment duration.

[002500] As non-limiting examples, any of the above-described methods featuring an IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen can be modified to replace the subject IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen with an IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen comprising: (a) administering a dosage of IFN-y containing an amount of 100 zug of drug per dose, subcutaneously three times per week; (b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; and (c) a dosage of pirfenidone or a pirfenidone analog containing a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, optionally in two or more divided doses per day; for the desired treatment duration.

[002501] As non-limiting examples, any of the above-described methods featuring an IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen can be modified to replace the subject IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen with an IFN-y, pirfenidone or pirfenidone analog, and NAC combination regimen comprising : (a) administering a dosage of IFN-y containing an amount of 200 ßg of drug per dose, subcutaneously three times per week ; (b) a dosage of NAC containing an amount of from about 500 mg to about 3000 mg per day, administered orally, optionally in two or more divided doses per day; and (c) a dosage of pirfenidone or a pirfenidone analog containing a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, optionally in two or more divided doses per day; for the desired treatment duration.

[002502] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear) -ylated consensus IF N-a with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 u, g to 360 p-g, or 180, ug, of drug per dose, subcutaneously once weekly for the desired treatment duration.

[002503] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 0.5 u. g to 2. 0 gag, or 1.0 pg to 1. 5 J, g, of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.

[002504] As non-limiting examples, any of the above-described methods that includes an endothelin receptor antagonist regimen can be modified to replace the subject endothelin receptor antagonist regimen with an endothelin receptor antagonist regimen comprising administering a dosage of Tracleer containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer containing an amount of 125 mg of drug orally twice per day for the remainder of the desired treatment duration.

[002505] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear) -ylated consensus IFN-a comprising administering an amount of monoPEG (30 kD, linear) -ylated consensus IFN-a once weekly or once every 8 days can be modified to administer the amount of monoPEG (30 kD, linear) -ylated consensus IFN-a once every 10 days for the desired treatment duration.

[002506] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 400 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002507] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 800 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002508] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 1000 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002509] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002510] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 1600 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002511] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 1800 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002512] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 2400 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002513] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 2800 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002514] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 3200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002515] As non-limiting examples, any of the above-described methods that includes a pirfenidone or pirfenidone analog regimen can be modified to replace the subject pirfenidone or pirfenidone analog regimen with a regimen of pirfenidone or pirfenidone analog comprising administering a dosage of 3600 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[002516] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 500 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002517] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 750 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002518] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 1000 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002519] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 1200 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002520] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 1500 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002521] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 1800 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002522] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 2000 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[0025231 As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 2500 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002524] As non-limiting examples, any of the above-described methods can be modified to replace the subject NAC regimen with a NAC regimen comprising administering a dosage of 3000 mg NAC orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[002525] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

SUBJECTS SUITABLE FOR TREATMENT [002526] Individuals who are suitable for treatment according to a subject method for treating a fibrotic disorder include individuals who have been clinically diagnosed with fibrosis, as well as individuals who have not yet developed clinical fibrosis but who are considered at risk of developing fibrosis.

[002527] The subject methods for treating IPF are suitable for treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were previously treated with corticosteroids within the previous 24 months, and who failed to respond to previous treatment with corticosteroids. Subjects that are particularly amenable to treatment with a method are those that have at least 55% of the predicted FVC. Also suitable for treatment are subject that have at least 60% of the predicted FVC ; or from 55% to 70% of the predicted FVC. The percent predicted FVC values are based on normal values, which are known in the art. See, e. g. , Crapo et al. (1981) Am. Rev. Respir. Dis. 123: 659-664. FVC is measured using standard methods of spirometry. Other subjects that are suitable for treatment have carbon monoxide diffusing capacity (DLco) 25% of predicted, e. g., 2 30% of predicted, or : 35% of predicted. Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) &gt; 25%, or &gt; 35%, of predicted normal DLCO. Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLCo &gt; 35% of predicted normal DLCo and (2) an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLCo &gt; 30% of predicted normal DLco and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

[002528] Individuals who are suitable for treatment with a subject method for treating cancer include individuals having any type of cancer, including individuals who have been diagnosed with a cancer and who have not yet been treated for the cancer ; individuals who have been diagnosed with a cancer, and who have been treated for the cancer with a treatment regimen other than a subject treatment regimen, including individuals who have failed previous treatment regimens for the cancer; and individuals who have been diagnosed with a cancer, and who have been treated with the cancer such that the cancer is in remission, but who are at risk for re-growth of the cancer.

[002529] Individuals who are suitable for treatment with a subject method for treating an angiogenic disorder include individuals having any type of angiogenic disorder, including individuals who have been diagnosed with an angiogenic disorder and who have not yet been treated for the angiogenic disorder; individuals who have been diagnosed with an angiogenic disorder, and who have been treated for the angiogenic disorder with a treatment regimen other than a subject treatment regimen, including individuals who have failed previous treatment regimens for the angiogenic disorder.

EXAMPLES [002530] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed.

Efforts have been made to ensure accuracy with respect to numbers used (e. g. amounts, temperature, etc. ) but some experimental errors and deviations should be accounted for.

Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

Example 1: Effect of IFN-ylb on TGF-p-induced ECM accumulation [002531] IPF is a crippling disease that impairs gas exchange in the lung due to excessive accumulation of extra cellular matrix (ECM). IPF is thought to result from epithelial cell injury followed by aberrant wound healing. Numerous resident and recruited cell types, including lung epithelial cells, fibroblasts, activated macrophages, platelets, and lymphocytes, are known to release transforming growth factor beta (TGF-beta) in lung tissue in individuals with IPF.

TGF-beta, in turn, enhances the deposition and accumulation of ECM, which leads to fibrotic lesions. To examine the molecular consequences of therapeutic application of IFN-gamma I b, the effect of IFN-gamma lb on TGF-beta-modulated ECM turnover was studied in a cellular model of IPF.

Methods [002532] A human lung epithelial cell line (A549) was cultured in DMEM culture medium containing 10% serum, then washed with phosphate-buffered saline (PBS); afterwards, serum- free medium was added to the cells. After overnight incubation in the serum-free medium, cells were treated with increasing concentrations of IFN-gamma lb, or left untreated, and then stimulated with 5 ng/ml TGF-beta. Both cell culture supernatant and cell lysate were collected, and enzyme-linked immunosorbent assay (ELISA) was used to quantify secreted collagen and intracellular tissue inhibitor of metalloproteases 1 (TIMP1).

Results [002533] Relative to untreated cells, TGF-beta induced the expression of collagen by 30% and TIMP 1 by 60 %. TGF-beta-induced expression of both collagen and TIMP 1 was suppressed in a concentration-dependent fashion by addition of IFN-gammalb (p 0.01 for TIMP1 and 0.03 for collagen). Importantly, these effects were statistically significant at the therapeutically relevant Cm", concentrations of IFN-gammalb obtained from clinical trials.

[002534] These results indicate that IFN-gammalb inhibits both TGF-beta-induced collagen synthesis and TGF-beta-induced accumulation of TIMP1. Since both of these components are integral to deposition and accumulation of extracellular matrix (ECM), the likely net result may be a substantial decrease in the rate of ECM accumulation. These results suggest that IFN-gammalb may be beneficial in the treatment for IPF in certain patients by reducing the rate of TGF-beta-induced ECM accumulation.

Example 2: Pirfenidone inhibits SAPK enzymatic activity [002535] Enzymatic activity of various human kinases was assayed in the presence and the absence of pirfenidone. Percent enzyme activity of various human enzymes in the presence of substrate and pirfenidone are shown in Figures 1-5, and in Table 2, below, where"percent enzyme activity"is the percent of the control activity (e. g. , in the absence of pirfenidone) : Table 2 Target enzyme % Activity SAPK3 46 CSK 64 SAPK2a 70 SAPK2ß 74 Syk 78 MKK6 84 CHK2 84 Bmx 86 CDK3/cyclinE 86 Rskl 88 PKBα 88 PKBß 88 PKC# 88 Fes 88 CDK2/cyclinE 89 PRK2 90 ROCK-II 90 IKKß 90 PRAK 90 GSK3α 91 GSK3ß 91 c-RAF 91 cSRC 91 Lyn 92 CDK2/cyclinA 92 CDK7/cyclinD3 92 IGF-1R 92 PAK2 93 MSK1 93 Axl 93 PDK1 93 PKCα 94 CK2 94 CDK7/cyclinH/MATl 95 PKCa 96 PKC# 96 p70S6K 96 PKC 96 JNK2 97 IR 97 Fyn 97 MAPKAP-K2 97 SAPK4 98 MAPK1 98 PKD2 98 Rsk2 99 PKCßII 100 MAPK2 100 MEK1 100 PDGFR 101 TrkB 101 PDGFRß 101 CDKl/cyclinB 102 CDK5/cyclinB 102 PKC# 102 Flt3 103 FGFR3 104 Yes 104 Lck 104 CHO1 105 MKK7P105 JNK1 105 JNK3 106 SGK 106 PKCo 106 CaMKIV 107 ZAP-70 109 PKA 109 PKBγ 111 IKKå 114 Rsk3 115 Aurora-A 120 [002536] The data indicate that pirfenidone is an inhibitor of SAPK, but does not substantially inhibit other kinases tested.

Example 3: Pirfenidone does not affect IFN-y-induced STAT1 tyrosine phosphorylation MATERIALS AND METHODS Cytokines, Antibodies, and Reagent [002537] Tissue culture plates were purchased from Falcon (Lincoln Park, NJ). DMEM (Dulbecco's Modified Eagle's Medium) and other cell culture reagents, polyacrylamide gel electrophoresis (PAGE) reagents were purchased from Sigma (St. Louis, MO). IFN-y (Actimmune IFN-&gamma; lb) and Pirfenidone were from InterMune, Inc. The anti-human phospho-STAT1 and STAT1 antibodies and horse-radish peroxidase-coupled secondary Abs were purchased from Cell Signaling (Beverly, MA). Nitrocellulose sheets (Hybond-C Ext), ECL reagents and X-Ray films were purchased from Amersham (Aylesbury, United Kingdom).

Testing the effect of Pirfenidone on STAT1 tyrosine phosphorylation [002538] ME180 cells were grown in DMEM supplemented with 10% heat inactivated fetal calf serum, 2 mM L-glutamine, streptomycin (100 g/ml) and penicillin (100 units/ml). Briefly, cells were seeded at a density of 5x 106 cells in 100 mm tissue culture dishes. After 24 hrs, cells were washed with phosphate-buffered saline (PBS) and incubated in serum free growth media for 16 hours, then treated with medium or with 100 µg/ml of Pirfenidone (PFD) for 1 h before treating them with Actimmune IFN-y lb ("IFN-g"in Figure 6 ; 10 ng/ml) for 0-10-20- 40 and 60 min. At the end of incubation period, cells were lysed by incubation in 50 mM HEPES (pH 7.0) containing 100 mM NaCl, 1.2% Triton X-100,10% glycerol, 1.5 mM MgCl2, 100 mM NaF, 10 mM sodium pyrophosphate, 1 mM sodium orthovanadate, 1 mM EGTA (ethylene glycol-bis-p-aminoethylether-tetraacetic acid), 1 mM DTT (dithiothreitol), 1mM phenylmethylsulfonylfloride, 0.15 unit/ml aprotinin, 10 pg/ml leupeptin, 10 llg/ml pepstatin.

Lysates were clarified by centrifugation (12.000 x g for 1 min. ). Equal amounts (100 J, g) total proteins were subjected to sodium dodecyl sulfate (SDS) -PAGE on 10 % polyacrylamide gels to separate the proteins. The proteins were then electrophoretically transferred from the polyacrylamide gel onto a nitrocellulose sheet for overnight at 20 mAmp, and analyzed by immunoblotting with anti-phospho STAT1 (Phos. STATl)-specific antibody (antibody specific for phosphorylated STAT1). The blot was then stripped off and re-labeled with STAT1 antibody for even loading. The results are shown in Figure 6.

[002539] As shown in Figure 6, pirfenidone does not affect IFN-y-induced STAT1 tyrosine phosphorylation.

Example 4: Assaying SAPK activity in peripheral blood mononuclear cells Materials and Methods Cytokines, Antibodies, and Reagent l002540] Tissue culture flasks are purchased from Falcon (Lincoln Park, NJ). RPMI-1640 growth medium and other cell culture reagents, PAGE reagents and TNF-a are purchased from Sigma (St. Louis, MO). The anti-human monoclonal antibody for CREB, and protein A/G-agarose are purchased from Santa Cruz Biotechnology (Santa Cruz, CA). y-32P-ATP, Nitrocellulose sheets (Hybond-C Ext) and enhanced chemiluminescence (ECL) reagents are purchased from Amersham (Aylesbury, United Kingdom).

Cell culture and treatments : [002541] Peripheral Blood Mononuclear Cells (PBMC) are collected from patients treated with Pirfenidone (600 mg/3 times/d) or with placebo. PBMC are incubated in RPMI-1640 supplemented with 10% heat inactivated fetal calf serum, 2 mM L-glutamine, streptomycin (100 ug/ml) and penicillin (100 units/ml) for 3 hours. Then, 2x107 cells are treated with 1, uM -32P-ATP and TNF-a (10 ng/ml) for 0 minutes, 5 minutes, 15 minutes, 30 minutes, or 45 minutes. At the end of the incubation period, cells are lysed by incubation in 50 mM HEPES (pH 7.0) containing 100 mM NaCl, 1.2% Triton X-100, 10% glycerol, 1.5 mM MgCl2, 100 mM NaF, 10 mM sodium pyrophosphate, 1 mM sodium orthovanadate, 1 mM EGTA (ethylene glycol-bis-, B-aminoethylether-tetraacetic acid), 1 mM DTT, 1mM phenylmethylsulfonylfloride, 0.15 unit/ml aprotinin, 10 llg/ml leupeptin, and 10 p. g/ml pepstatin. Lysates are clarified by centrifugation (12.000 x g for 1 min. ). Next, 3 mg of lysate are pre-cleared with 100 ; j, l of protein A/G agarose beads for 1 h. at 4°C. Next, samples are centrifuged, 3 u. g ofanti CREB antibodies are added to supernatants, and samples are shaken at 4°C for 4 h. Next, 100 ul of protein A/G agarose beads are added and samples are shaken overnight at 4°C. Beads are precipitated by centrifugation, and washed three times with cell lysis buffer. Next, 100, ut of 2X SDS-loading dye are added onto the pellets, then samples are boiled for 5 min, and centrifuged. Equal amount of supernatants are subjected to SDS-PAGE on 10 % polyacrylamide gels to separate proteins. Following electrophoresis, the proteins are electrophoretically transferred from the acrylamide gel onto nitrocellulose sheet for overnight at 20 mAmp. X-Ray film is exposed to the blot and developed. Parallel to this, an identical gel is prepared from regular cellular lysate and the blot is labeled with anti CREB antibody to determine the exact position of CREB on the gel.

Results [002542] Transcription factor CREB is robustly activated by several stress inducing environmental stimuli, including TNF-a, UV-C, and osmotic shock. It is expected that there is very little phosphorylation of CREB before treatment of PBMC with TNF-a. It is expected that when PBMC are treated with TNF-a, the phosphorylation of CREB increases in a time- dependent manner with the highest level (-5 fold vs control) of phosphorylation at 15 min. It is also expected that TNF-a-induced phosphorylation of CREB in PBMC isolated from Pirfenidone treated patients is only-1. 5-2.0 fold higher than that of untreated cells.

[002543] The effect of Pirfenidone on the activity of SAPK2/3 is analyzed. It is expected that 100 Fg/ml of Pirfenidone inhibits the activity of SAPK2/3 by 50 % under in vitro condition. It is expected that the in vivo target of Pirfenidone is SAPK2/3.

Example 5: Analysis of pirfenidone inhibition ofp38y [002544] Pirfenidone inhibition of p38y (SAPK3) was analyzed. The results are depicted in Figures 7-9. The results indicate that: 1) pirfenidone does not inhibit SAPK3 by aggregation or any other non-specific molecular effect; 2) pirfenidone is a competitive inhibitor of ATP ; 3) pirfenidone binds SAPK3 only after the phosphorylation substrate binds. Since it is known that ATP can only bind after the phosphorylation substrate binds, the results imply that pirfenidone binds directly to the ATP binding site.

[002545] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.