ANTI IL-17 ANTIBODY FOR USE IN TREATING CHRONIC SPONTANEOUS

URTICARIA

TECHNICAL FIELD

The present disclosure relates generally to the use of an anti-IL-17 antibody as a therapeutic tool in patients suffering from (severe) chronic spontaneous urticaria (CSU).

BACKGROUND

Chronic spontaneous urticaria (CSU) is considered in about 50% of patients to be an autoimmune disorder. Initially, it was characterized by the detection of positive autologous skin serum test (ASST), later defined as the presence of IgG autoantibodies against FcsRIa on skin mast cells and basophils. This was recently defined as type II autoimmunity. In many other CSU patients, IgE autoantibodies against thyroid peroxidase are detected, inducing auto-allergic mast cell activation and degranulation, and defined as type I autoimmunity (1-3). In parallel with the above evidences on autoimmunity and its role in CSU, CD4+ T cells were also reported to be involved. The finding of activated CD4+ T cells in peripheral blood as well as in skin biopsies of CSU patients provided a good explanation to why severe patients responded well to cyclosporine A when high doses of anti-histamines were insufficient (4-6). T regulatory cells (CD4+CD25+FoxP3+ T cells) (Tregs), as well as serum levels of interleukin -10 were shown to be altered in CSU patients and in correlation with disease severity, giving a wider understanding for T cell involvement in CSU (7). T-cell responses against FcsRIa have been analyzed by assessing their specific proliferation and cytokine secretion. Peripheral CD4+ T cell proliferation was documented in 27% of patients and in none of healthy controls. IFN-v responses to FcsRIa were found in 53% of patients and autoantibodies to FcsRIa in 43% suggesting that T cell over activity and autoimmunity are combined pathogenic factors in CSU and of high diagnostic sensitivity and specificity (8). Serum concentration of IF- 17, IF-23 and TNF among patients with chronic spontaneous urticarial were reported (9). The relationship between circulating concentrations of interleukin- 17 and C-reactive protein in chronic spontaneous urticaria was reported (10). Different expression of plasma Thl, Th2, Thl7 and Th22-related cytokines correlate with serum autoreactivity and allergen sensitivity in chronic spontaneous urticaria were reported (11). Thl/Th2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria were reported (12).

Interleukin 17A (IL-17 or IL-17A) is a pro-inflammatory cytokine. This cytokine is produced by a group of T helper cells. A biologically active IL-17 interacts with type I cell surface receptor IL-17R, which has at least three variants namely, IL17RA, IL17RB, and IL17RC. After binding to the receptor, IL-17 activates several signaling pathways that lead to the induction of chemokines, which can recruit the immune cells, such as monocytes and neutrophils to the site of inflammation. In some instances, activation of IL-17 signaling is observed in the pathogenesis of various immune mediated/autoimmune disorders, such as, psoriatic arthritis, rheumatoid arthritis and others. Various antagonists and antibodies targeting IL-17 have been developed over the years. For example, US Patent. No. 7,807,155 is directed to IL-17 antagonistic antibodies. For example, US Publication No. US20100266531 is directed to IL-17 binding proteins. For example, US Publication No. US20150147327 is directed to dual variable domain immunoglobulin and uses thereof. For example, US Publication No. US20070160576A1 is directed to IL-17A/F heterologous polypeptides and therapeutic uses thereof. For example, EP Application No. EP3130604A1 is directed to anti-IL-17 antibodies, method for producing same and method for using same.

To name a few, current treatments for CSU include the use of antihistamines, steroids, cyclosporine A, Leukotriene receptor antagonists (LTRAs) and Omalizumab ((Xolair, a recombinant humanized monoclonal antibody binding the CH3 domain of the e chain of IgE). However, such treatments exhibit side effects or in many cases are not efficient in controlling and reducing disease severity. For example, in the case of Omalizumab, 15-17% of patients- are considered to be non-responders to this treatment.

Thus, there is a need in the art for improved compositions and methods for treating CSU, which are safe and effective, have minimal side effects and which can enhance the beneficial outcome of such therapy. SUMMARY

Aspects of the disclosure, according to some embodiments thereof, relate to the advantageous use of an anti-IL-17 antibody for the treatment of Chronic Spontaneous Urticaria (CSU). More specifically, but not exclusively, aspects of the disclosure, according to some embodiments thereof, relate to compositions and methods utilizing anti-IL-17 antibody for the treatment of CSU.

According to some embodiments, there is provided a method for treating, preventing, inhibiting, ameliorating and/or reducing the severity and/or occurrence of Chronic spontaneous urticaria (CSU) and/or at least one symptom associated with CSU in a subject in a need thereof, the method includes administering to the subject a therapeutically effective amount of anti-IL-17 antibody, or a pharmaceutical composition comprising the same.

According to some embodiments, the reduction in severity of CSU disease may be determined by reduction or change in the UAS7 of the patient, as detailed below and/or any related parameter, including, for example, but not limited to: Urticaria Control Test (UCT), visual inspection and/or Quality of life questioner. In some embodiments, the administration is systemic. In some embodiments, the administration is parenteral, such as, by injection or by intravenous administration. In some embodiments, the administration is performed at least two consecutive times at a desired time interval (such as about 1-2 weeks) between administrations.

According to some embodiments, there is provided a method for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence and/or severity of Chronic spontaneous urticaria (CSU) and/or at least one symptom associated with CSU in a subject in a need thereof, the method includes systemically administering to the subject a therapeutically effective amount of an anti-IL-17 antibody, wherein the anti-IL-17 antibody is administered at least two times.

According to some embodiments, the administering of the anti-IL-17 antibody to the subject may be repeated at least three times. In some embodiments, a time interval between two consecutive administering of the anti-IL-17 antibody may be in the range of about 7 to 14 days.

According to some embodiments, the anti- IL-17 antibody may be administered once about every 1, 2, 3, or 4 weeks. In some embodiments, the anti-IL-17 antibody may be administered once about every 1, 2, 3, 4, 5, 6 months or more. According to some embodiments, the anti- IL-17 antibody may be administered once about every 1-2 weeks for about 4-8 weeks and then once about every 2 weeks to 3 months for about 6-12 months or more. According to some embodiments, the anti- IL-17 antibody may be administered once about every week for about four weeks and then once about every two weeks for about six months or more.

According to some embodiments, the anti-IL-17 antibody may be administered at a dose of about 100mg-300mg per administration. According to some embodiments, the anti-IL-17 antibody may be administered at a dose of about 150mg per administration.

According to some embodiments, the anti- IL-17 antibody may be administered at a dose ranging from at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight. According to some embodiments, the anti- IL-17 antibody may be administered at a dose ranging from at least about 1 mg/kg to at least about 3 mg/kg body weight.

According to some embodiments, the method may further include administering to the subject a therapeutically effective amount of a second therapeutic agent selected from the group consisting of: an anti-inflammatory, antihistamine drug or any combination thereof. In some embodiments, the anti-inflammatory drug is a steroid drug. In some embodiments, the second therapeutic agent may be selected from: Omalizumab, Montelukast, Cyclosporin, Azathioprine, Methotrexate or any combination thereof.

In some embodiments, the second therapeutic agent may be administered concomitantly with the anti-IL-17 antibody.

According to some embodiments, the severity of the CSU condition may be determined according to urticaria activity score (UAS7). In some embodiments, a reduction in the UAS over a time period is indicative of treatment efficacy. In some embodiments, the severity of the CSU may be determined according to cumulative UAS over 7 days (UAS7) and wherein a reduction in UAS7 over a time period is indicative of treatment efficacy.

According to some embodiments, the anti-IL-17 antibody may be comprised in a pharmaceutical composition. In some embodiments, the anti-IL-17 antibody may be administered parenterally, by injection.

In some embodiments, the IL-17 antibody may be selected from, but not limited to: Secukinumab (Cosentyx), ixekizumab (Taltz) and Brodalumab (Siliq). In some exemplary embodiments, the IL-17 antibody is Secukinumab.

According to some embodiments, there is provided an anti-IL-17 antibody for use in treating, preventing, inhibiting, ameliorating and/or reducing the occurrence and/or severity of Chronic spontaneous urticaria (CSU) or at least one symptom associated with CSU in a subject in a need thereof, wherein the anti-IL-17 antibody is administered systemically to the subject at least two times.

According to some embodiments, the anti-IL-17 antibody may be administered to the subject at least three times. According to some embodiments, a time interval between two consecutive administrations of the anti-IL-17 antibody is in the range of about 7 to 14 days. According to some embodiments, the anti- IL-17 antibody may be administered once about every 1, 2, 3, or 4 weeks. In some embodiments, the anti- IL-17 antibody may be administered once about every 1, 2, 3, 4, 5, 6 months or more. In some embodiments, the anti- IL-17 antibody may be administered once about every 1-2 weeks for about 4-8 weeks and then once about every 2 weeks - 3 months for about 6-12 months or more. In some embodiments, the anti- IL-17 antibody may be administered once about every 7 days for about four weeks and then once about every 14 days for about six months or more.

In some embodiments, the anti-IL-17 antibody may be administered at a dose of about 100 mg-300 mg per administration. In some embodiments, the anti-IL-17 antibody may be administered at a dose of about 150 mg per administration. In some embodiments, the anti- IL-17 antibody may be administered at a dose ranging from at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight, or at least about 1 mg/kg to at least about 3 mg/kg body weight.

According to some embodiments, the anti-IL-17 antibody for use may be further accompanied with administration of therapeutically effective amount of a second therapeutic agent selected from the group consisting of: an anti-inflammatory, antihistamine drug or any combination thereof. In some embodiments, the anti-inflammatory drug may be a steroid drug. In some embodiments, the second therapeutic agent may be: Omalizumab, Montelukast, Cyclosporin, Azathioprine, Methotrexate or any combination thereof. In some embodiments, the second therapeutic agent may be administered concomitantly with the anti-IL-17 antibody.

According to some embodiments, the severity of the CSU condition may be determined according to urticaria activity score (UAS). In some embodiments, a reduction in the UAS over a time period is indicative of treatment efficacy. In some embodiments, the severity of the CSU may be determined according to cumulative UAS over 7 days (UAS7) and wherein a reduction in UAS7 over a time period is indicative of treatment efficacy. According to some embodiments, the anti-IL-17 antibody may be comprised in a pharmaceutical composition, which further includes one or more pharmaceutically acceptable carriers.

According to some embodiments, there is provided a kit which includes: (a) at least one dosage ranging from about 1 mg to about 500 mg of an anti-IL-17 antibody; and (b) instructions for using the anti-IL-17 antibody for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence and/or severity of Chronic spontaneous urticaria (CSU) or at least one symptom associated with CSU in a subject in a need thereof.

According to some embodiments, the dosage of the anti-IL-17 antibody in the kit ranges from about 100 mg to about 300 mg. In some embodiments, the dosage of the anti-IL-17 antibody is about 150 mg.

According to some embodiments, the instructions of the kit may further include instructions to administer the anti-IL-17 antibody to the subject at least two times. According to some embodiments, a time interval between two consecutive administrations may be in the range of about 7-14 days.

According to some embodiments, the anti-IL-17 antibody may be included in a pharmaceutical composition which may further include one or more pharmaceutically acceptable carriers

Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more other technical advantages may be readily apparent to those skilled in the art from the figures, descriptions, and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some, or none of the enumerated advantages.

Unless otherwise defined, 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 disclosure pertains. In case of conflict, the patent specification, including definitions, governs. As used herein, the indefinite articles“a” and“an” mean“at least one” or“one or more” unless the context clearly dictates otherwise.

BRIEF DESCRIPTION OF THE FIGURES

Some embodiments of the disclosure are described herein with reference to the accompanying figures. The description, together with the figures, makes apparent to a person having ordinary skill in the art how some embodiments may be practiced. The figures are for the purpose of illustrative description and no attempt is made to show structural details of an embodiment in more detail than is necessary for a fundamental understanding of the disclosure. For the sake of clarity, some objects depicted in the figures are not to scale.

In the Figures:

Fig. 1A is an exemplary immunofluorescent staining of CD4+T cells in a skin biopsy of a healthy subject, according to some exemplary embodiments;

Fig. IB is an exemplary immunofluorescent staining of CD4+T cells in a skin biopsy of a CSU patient, according to some exemplary embodiments;

Fig. 1C is a histogram depicting the number of CD4+T cells in CSU skin biopsies (mean 50±6 cells\slide) as compared to normal skin biopsies (mean 7± 2 cells\slide), p=0.0002, according to some exemplary embodiments;

Fig. 2A is an exemplary immunofluorescent staining of CD117+ (cKit) mast cells in a biopsy of a healthy subject, according to some exemplary embodiments; Fig. 2B is an exemplary immunofluorescent staining of CD117+ (cKit) mast cells in skin biopsy of a CSU patient, according to some exemplary embodiments;

Fig. 2C is a histogram depicting the number of CD117+ (cKit) mast cells in CSU skin biopsies (mean 200±20 cells\slide) as compared to normal skin biopsies (mean 40±10 cells\slide), p=0.0099, according to some exemplary embodiments;

Fig. 3A is an exemplary IL-17 immunohistochemistry of a skin biopsy of a healthy subject, according to some exemplary embodiments;

Fig. 3B is an exemplary IL-17 immunohistochemistry of a skin biopsy of a CSU patient shown at X20 magnification, according to some exemplary embodiments; Fig. 3C is an exemplary IL-17 immunohistochemistry of a skin biopsy of a CSU patient shown at X40 magnification, according to some exemplary embodiments;

Fig. 4A depicts positive IL-17 stained cells in a skin biopsy of a CSU patient (Arrow No. l denotes mast cell in proximity to positive stained CD4 lymphocytes - Arrows No.2) at X200 magnification, according to some exemplary embodiments; Fig. 4B depicts IL-17 stained cells in A skin biopsy of a CSU patient (Arrow No. 3 denotes mast cells, Arrow No. 4 denotes endothelial cells and Arrows No. 5 and 6 denote lymphocytes) at X400 magnification, according to some exemplary embodiments;

Fig. 5 - Line graphs showing UAS7 score of 8 treated patients at the beginning of treatment (“Day 0”), 30 days (“Day 30”) and 90 days (“Day 90”) after commencement of treatment; and Figs. 6A-6F- pictograms of skin regions of various body parts of CSU patients, before treatment (Figs. 6A, 6C and 6E) and after 30-60 days from commencement of treatment with anti-IL-17 antibody (Figs. 6B, 6D and 6F, respectively). DETAILED DESCRIPTION

The principles, uses and implementations of the teachings herein may be better understood with reference to the accompanying description and figures. Upon perusal of the description and figures present herein, one skilled in the art will be able to implement the teachings herein without undue effort or experimentation.

According to some embodiments, there are provided methods and compositions for treating, ameliorating and/or reducing severity of chronic spontaneous urticaria (CSU) in a subject afflicted with CSU, by systemically administering to a subject an IL-17a antibody or a composition comprising the same, wherein the antibody is administered at a therapeutically effective dose, which do not induce side effects and wherein the administration is repeated at least two consecutive times, at desired time intervals.

According to some embodiments, without wishing to be bound to any theory or mechanism, the present inventors have demonstrated for the first time the expression of IL-17 (Interleukin 17) on skin mast cells in CSU patients. Further, it was evidenced that IL-17 expressing T and mast cells are located in close proximity thereto in the skin of CSU patients, indicating that this phenomenon is of mechanistic importance. It was also surprisingly found that IL-17 expressing CD4+ T cells and mast cells are found in similar intensity in lesional and non-lesional skin regions of CSU patients, but not in skin from healthy subjects, thus indicating that the skin of CSU patients is permanently infiltrated with immune cells. The importance of the finding presented herein, in accordance with some embodiments, is that together with the intense infiltration of IL-17 expressing CD4+ T cells in the skin of CSU patients, the new evidence of IL-17 expression on skin mast cells in CSU that is shown for the first time provide a role for anti-IL17 therapy in treating CSU. Thus, advantageously, the inventors have shown for the first time a safe and effective systemic treatment of CSU patients using anti-IL17 antibody, as determined by various parameters, including, skin appearance, patient well-being questioners as well as dramatic changes in UAS7 score. All in all, as embodied herein, the results presented in the examples below substantiate the role for anti-IL-17 agents, such as IL-17a antibody in treating CSU and demonstrate an effective and safe treatment. Definitions

To facilitate an understanding of the present invention, a number of terms and phrases are defined below. It is to be understood that these terms and phrases are for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance presented herein, in combination with the knowledge of one of ordinary skill in the art.

As used herein, the term "antibody" (Ab) includes, without limitation, a glycoprotein immunoglobulin which binds specifically to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen- binding portion thereof. Each H chain comprises a heavy chain variable region and a heavy chain constant region. The heavy chain constant region comprises at least three constant domains, Cm, CHI and Cm- Each light chain comprises a light chain variable region and a light chain constant region. The light chain constant region comprises one constant domain. The YH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each YH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgGl) that is encoded by the heavy chain constant region genes. The term "antibody" includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or non-human antibodies; wholly synthetic antibodies; and single chain antibodies. A non-human antibody can be humanized by recombinant methods to reduce its immunogenicity in man. Where not expressly stated, and unless the context indicates otherwise, the term "antibody" also includes an antigen- binding fragment or an antigen-binding portion of any of the aforementioned immunoglobulins, and includes a monovalent and a divalent fragment or portion, and a single chain antibody. The term "antibody" is used in the broadest sense and includes monoclonal antibodies (including full length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multi specific antibodies (e.g., bi-specific antibodies), and antibody fragments long enough to exhibit the desired biological activity. The antibody according to the present invention is a molecule comprising at least the antigen-binding portion of an antibody. Antibody or antibodies according to the invention include intact antibodies, such as polyclonal antibodies or monoclonal antibodies (mAbs), as well as proteolytic fragments thereof, such as the Fab or F(ab')2 fragments. Single chain antibodies also fall within the scope of the present invention.

An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that binds specifically to IL-17 is substantially free of antibodies that bind specifically to antigens other than IL-17. An isolated antibody that binds specifically to IL-17 can, however, have cross-reactivity to other antigens, such as IL-17 molecules from different species. Moreover, an isolated antibody can be substantially free of other cellular material and/or chemicals.

The term "monoclonal antibody" (mAb) refers to a non-naturally occurring preparation of antibody molecules of single molecular composition, i.e., antibody molecules whose primary sequences are essentially identical, and which exhibits a single binding specificity and affinity for a particular epitope. A monoclonal antibody is an example of an isolated antibody. mAbs can be produced by hybridoma, recombinant, transgenic, or other techniques known to those skilled in the art. The mAbs of may be of any immunoglobulin class including IgG, IgM, IgE, IgA.

A "human antibody" (HuMAb) refers to an antibody having variable regions in which both the FRs and CDRs are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The human antibodies of the disclosure can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). The term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms "human antibodies" and "fully human antibodies" are used synonymously.

A "humanized antibody" refers to an antibody in which some, most or all of the amino acids outside the CDRs of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an antibody, some, most or all of the amino acids outside the CDRs have been replaced with amino acids from human immunoglobulins, whereas some, most, or all amino acids within one or more CDRs are unchanged. Small additions, deletions, insertions, substitutions, or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen. A "humanized antibody" retains an antigenic specificity similar to that of the original antibody. In some embodiments, the CDRs of a humanized antibody contain CDRs from a non human, mammalian antibody. In other embodiments, the CDRs of a humanized antibody contain CDRs from an engineered, synthetic antibody.

A "chimeric antibody" refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.

An "antigen-binding portion" of an antibody (also refers an "antigen -binding fragment") refers to one or more fragments of an antibody that retain the ability to bind specifically to the antigen bound by the whole antibody.

The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" is not to be construed as requiring production of the antibody by any particular method. mAbs may be obtained by methods known to those skilled in the art. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et ah, Nature 1975, 256, 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson et ah, Nature 1991, 352, 624-628 or Marks et ah, J. Mol. Biol., 1991, 222:581-597, for example.

The terms "anti IL-17 antibody", “"anti-IL-17 antibody”, “anti-IL-17” and “IL-17 antibody” may interchangeably be used. The terms refer to an antibody (or an antigen binding fragment thereof) that binds specifically to the IL-17 protein. In some embodiments, the IL-17 antibody binds, recognizes or directed against human IL-17a protein (antigen). In some embodiments, the IL-17 antibody is capable of interfering or otherwise inhibiting activity, function or binding of IL-17. In some embodiments, the IL-17 antibody has the ability to substantially antagonize, prohibit, prevent, restrain, slow, disrupt, eliminate, stop, reverse biological activity or property of IL-17. In some embodiments, the IL-17 antibody is capable of affecting the binding of IL-17 to its cognate receptor (IL-17r). In some embodiments, the anti- IL-17 antibody is a monoclonal antibody. In some embodiments, the anti-IL-17 antibody is a chimeric antibody. In some embodiments, the IL-17 antibody is a humanized antibody. In some embodiments, the IL-17 antibody is a partially humanized antibody. In some exemplary embodiments, an IL-17 antibody (and specific CDRs thereof) is disclosed in any one of: US Patent No. 7,807, 155, US Publication No. US20100266531, US Publication No. US20070160576A 1 , EP Patent Application No. EP3130604A1, US Patent No. US 7,838,638, the contents of any of which are incorporated herein in their entirety.

In some embodiments, the IL-17 antibody may be selected from, but not limited to: Secukinumab (Cosentyx™), ixekizumab (Taltz™) and Brodalumab (Siliq™). Each possibility is a separate embodiment. In some exemplary embodiments, the IL-17 antibody is Secukinumab.

As used herein, the terms“IL-17”,“IL17” and“Interleukin 17” may interchangeably be used. In some embodiments, IL-17 is IL-17A. According to some embodiments, the term "Administering" refers to the physical introduction of the anti-IL-17 antibody or a composition comprising the same to a subject, using any of the various methods and delivery systems known to those skilled in the art. Routes of administration for the anti-IL-17 antibody include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, for example by injection or infusion. Each possibility is a separate embodiment. According to some embodiments, the term "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. Each possibility is a separate embodiment. In some embodiments, the composition may be administered via a non-parenteral route, in some embodiments, orally. Other non-parenteral routes may include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. In some embodiments, administering may be performed, for example, once, a plurality of times, and/or over one or more extended periods, as detailed below.

In some embodiments, the anti-IL-17 antibody (or a pharmaceutical composition comprising the same) is administered by injection. In some exemplary embodiments, the anti-IL- 17 antibody (or a pharmaceutical composition comprising the same) is administered by sub cutaneous (s.c.) injection.

According to some embodiments, therapeutic agents (i.e. IL-17 antibodies) of the present disclosure may be constituted in a composition, e.g., a pharmaceutical composition containing the antibody (or an antigen binding fragment thereof) and a pharmaceutically acceptable carrier. As used herein, a "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, the carrier for a composition containing an antibody is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). A pharmaceutical composition of the disclosure can include one or more pharmaceutically acceptable salts, anti-oxidant, aqueous and nonaqueous carriers, and/or adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.

Ain some embodiments, the IL-17 antibody can be incorporated into pharmaceutical compositions suitable for administration to a subject. The IL-17 antibody may be administered alone or in combination with a pharmaceutically acceptable carrier, diluent, and/or excipient, in single or multiple doses. The pharmaceutical compositions for administration are designed to be appropriate for the selected mode of administration, and pharmaceutically acceptable diluent, carrier, and/or excipients such as dispersing agents, buffers, surfactants, preservatives, solubilizing agents, isotonicity agents, stabilizing agents and the like are used as appropriate. A pharmaceutical composition comprising an anti-IL-17 antibody can be administered to a subject at risk for or exhibiting CSU pathologies as described herein using standard administration techniques including, but not limited to: subcutaneous, intravenous, intraperitoneal, transdermal, and intramuscular.

According to some embodiments, the term "subject" may include any human or non human animal. According to some embodiments, the terms, "subject" and "patient" may be used interchangeably.

According to some embodiments, the term "therapeutically effective amount" may be used interchangeably with the term "therapeutically effective dosage" and may refer to a therapeutic agent or drug in any amount of the agent that, when used alone or in combination with drugs, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, reduction or change in UAS or UAS7 score, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

According to some embodiments, the term "once about every week", "once about every 2 weeks", "once about every 3 weeks", "once about every 4 weeks", etc. or any other similar dosing interval terms as used herein mean approximate numbers. "Once about every week" can include every seven days ± one day, i.e., every six days to every eight days. "Once about every 2 weeks" can include every fourteen days ± three days, i.e., every eleven days to every seventeen days. Similar approximations apply, for example, to once about every 3 weeks, once about every 4 weeks, once about every 5 weeks, once about every six weeks and once about every 10 weeks. According to some embodiments, the interval between treatments may change during the overall course of treatment. For example, the patient may be heated every two weeks for the first 3 months and then every 3 weeks for the next 3 months of treatment or the patient may be treated once a week for the first 2 months and then every 2 weeks for the next 3 months of treatment. For example, the patient may be treated once a week for the first four weeks and then every 2 weeks for the next 6 months of treatment.

According to some embodiments, the terms“at least two consecutive times”,“at least twice”,“at least two times” with respect to administration of the IL-17 antibody or other drug refer to administration of the therapeutic agent in at least two separate administration events, having a temporal difference (time period or time interval) therebetween. For example, two consecutive times may be performed at a time interval of about 7 to 14 days between administrations. For example, two consecutive times may be performed at a time interval of about one to two weeks between administrations. For example, two consecutive times may be performed at a time interval of about 7 days or about one week between administrations. In some embodiments, the time intervals between sets of consecutive administrations are essentially the same (for example, about one week between administrations). In some embodiments, the time intervals between sets of consecutive administrations may vary (for example, about one week between a first administration and a second administration and about two weeks between a second administration and a third administration). In some embodiments, consecutive administration events may be identical, similar or different with respect of dosage, administration route, and/or administration regime (for example, the administration time (hour) of the day)).

As referred to herein, the term“UAS” is directed to“Urticaria Activity Score” which is used in the art to measure CSU disease severity and monitor treatment results in daily practice. The UAS assigns a score from 0 (no disease activity) to 3 (intense activity) for each of the 2 key urticaria symptoms, wheals and pruritus. The sum of the scores represents disease severity on a scale from 0 (minimum) to 6 (maximum). The term“UAS7” score is directed to the cumulative symptoms score over a time period of 7 days.

As referred to herein, the term“treating” with respect to CSU refers to one or more of: preventing, inhibiting, ameliorating and/or reducing the severity and/or occurrence of Chronic spontaneous urticaria (CSU) and/or at least one symptom associated with CSU in a subject in a need thereof. Each possibility is a separate embodiment. In some embodiments,“treatment”, “treating”, and the like, refer to obtaining a desired pharmacologic and/or physiologic effect on CSU. The effect may be prophylactic in terms of completely or partially preventing CSU or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for CSU. In some embodiments, treatment, includes administration of a IL-17 antibody for treatment of CSU, in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to; (b) inhibiting the disease, i.e., arresting its development; and/or (c) relieving the disease, i.e., causing regression or alleviating symptoms or complications thereof.

In some embodiments, in order to assess disease severity and/or treatment efficacy, one or more parameters related to CSU may be determined. In some embodiments, a change in one or more parameters is indicative of treatment efficacy. According to some exemplary embodiments, the reduction in severity of CSU disease may be determined by determining/calculating a reduction or change in the UAS or UAS7 of the patient. In some embodiments a reduction in UAS score of a subject of at least about 2%, 10%, 20%, 30% or over (compared to base-line UAS score (i.e., the score of the patient prior to treatment) is indicative of treatment efficacy. Each possibility is a separate embodiment. In some embodiments, a reduction in UAS7 score to a value of below about 30, below about 28, below about 25, below about 22, below about 20, below about 18, below about 15, below about 12, below about 10, or below about 8 is indicative of treatment efficacy. Each possibility is a separate embodiment. In some embodiments, a reduction in UAS score to a value of below about 6, below about 5, below about 4, below about 3, below about 2, or below about 1, is indicative of treatment efficacy. Each possibility is a separate embodiment. Each possibility is a separate embodiment. In some embodiments, the reduction in UAS or UAS7 may be determined over a time period. In some embodiments, the time period may be between a zero time point (beginning of treatment) and any time point after commencement of treatment (for example, 30 days, 60 days, 90 days, etc.). Additionally or alternatively, a change in other parameters related to CSU may be determined, including, for example, such parameters as, but not limited to: UAS7 cumulative score, (significant) improvement in angioedema attacks and/or severity.

According to some embodiments, disease severity may be determined by one or more of the parameters of: pruritus and urticarial rash, UAS7 score, angioedema severity and quality of life. Each possibility is a separate embodiment. Accordingly, in some embodiments, treatment efficacy may be determined based on a change in one or more of: pruritus and urticarial rash, UAS7 score, angioedema severity and quality of life. Each possibility is a separate embodiment.

In some embodiments, the subjects afflicted with CSU have been treated with other agents (including, for example, steroids, omalizumab, cyclosporine A) prior to being treated with antibody against IL-17 (anti IL-17 antibody).

In some embodiments, CSU subjects that have not responded or only partially responded to treatment with omalizumab exhibit an improved response to treatment with anti IL-17 antibody.

According to some embodiments, there is provided a combined treatment of anti-IL-17 with omalizumab, which in some instances may be beneficial when omalizumab treatment alone fails.

According to some embodiments, the method may further include administering to the subject a therapeutically effective amount of a second therapeutic agent selected from the group consisting of: an anti-inflammatory, antihistamine drug (regular does or high doses, on a regular/daily use) or any combination thereof. According to some embodiments, the anti inflammatory drug may include a steroid drug. According to some embodiments, the second therapeutic agent may include Omalizumab, Montelukast, Cyclosporin, Azathioprine, Methotrexate or any combination thereof. Each possibility is a separate embodiment.

In some embodiments, the second therapeutic agent may be administered together with the IL-17 antibody (in a single or separate compositions) and/or separately from the administration of the IL-17 antibody, at any suitable time interval, any suitable administration route and/or any suitable administration regime. According to some embodiments, there is provided a method for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence and/or severity of Chronic spontaneous urticaria (CSU) and/or at least one symptom associated with CSU in a subject in a need thereof. Each possibility is a separate embodiment.

According to some embodiments, there is provided a method for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence and/or severity of Chronic spontaneous urticaria (CSU) and/or at least one symptom associated with CSU in a subject in a need thereof, the method includes systemically administering to the subject a therapeutically effective amount of an anti-IL-17 antibody, wherein the administering is repeated at least two times.

According to some embodiments, there is provided an anti-IL-17 antibody (or an antigen binding portion thereof) for use in treating, preventing, inhibiting, ameliorating and/or reducing the occurrence or severity of Chronic spontaneous urticaria (CSU) or at least one symptom associated with CSU in a subject in a need thereof, wherein the anti-IL-17 antibody (or antigen binding portion thereof) binds specifically to IL-17 and affects the activity thereof.

According to some embodiments, there is provided an anti-IL-17 antibody for use in treating, preventing, inhibiting, ameliorating and/or reducing the occurrence or severity of CSU or at least one symptom associated therewith in a subject in a need thereof, wherein the anti-IL- 17 antibody is administered systemically at least twice and wherein the treatment efficacy is determined by a change (such as reduction) of UAS or UAS7 over time.

According to some embodiments, there is provided a use of anti-IL-17 antibody for the manufacture of a medicament for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence or severity of CSU or at least one symptom associated therewith in a subject in a need thereof, wherein the anti-IL-17 antibody is medicament may be systemically at least twice and wherein the treatment efficacy is determined by a change (such as reduction) of UAS or UAS7 over time.

According to some embodiments, there is provided an anti-IL-17 antibody for use in reducing UAS or UAS7 in a subject afflicted with CSU, wherein the anti-IL-17 antibody is administered systemically at least twice. According to some embodiments, there is provided a method for treating, preventing, inhibiting, ameliorating and/or reducing the severity or occurrence of CSU, or at least one symptom associated with CSU in a subject in a need thereof, the method includes systemically administering at least two times to the subject a therapeutically effective amount of an anti-IL-17 antibody (or antigen-binding fragment thereof).

According to some embodiments, there is provided a method for treating, preventing, inhibiting, ameliorating and/or reducing the severity or occurrence of CSU, or at least one symptom associated with CSU in a subject in a need thereof, the method includes systemically administering at least two times to the subject a therapeutically effective amount of an anti-IL-17 antibody, or antigen-binding fragment thereof, herein the treatment efficacy is determined by a change (such as reduction) of UAS or UAS7 over time.

According to some embodiments, there is provided a method for reducing UAS or UAS7 in a subject afflicted with CSU, the method includes systemically administering at least two times to the subject a therapeutically effective amount of an anti-IL-17 antibody (or antigen binding fragment thereof).

According to some embodiments, there is provided a pharmaceutical composition which includes a therapeutically effective amount of an anti-IL-17 antibody (or antigen -binding fragment thereof), for use in reducing UAS or UAS7 in a subject afflicted with CSU, wherein the pharmaceutical composition is administered systemically at least two times.

According to some embodiments, there is provided a pharmaceutical composition for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence and/or severity of CSU or at least one symptom associated with CSU in a subject in a need thereof, the pharmaceutical composition comprising a therapeutically effective amount of an anti-IL-17 antibody, or antigen-binding fragment thereof and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is administered systemically at least twice. In some embodiments, a change or reduction in UAS or UAS7 over time (along the course of treatment) is indicative of treatment efficacy (reduction in occurrence or severity of CSU). In some embodiments, the IL-17 antibody can be provided in a kit, a packaged combination of reagents, additives or excipients in predetermined amounts with instructions for performing the therapeutic procedure. Exemplary additives that may be included in the kit can include stabilizers, buffers and the like. The reagents in the kit may be provided as ready for use solutions or in some instances as dry powders, lyophilized, including excipients which on dissolution will provide a reagent solution having the appropriate concentration.

In some embodiments, the anti IL-17 in the kit may be stored in suitable containers including, for example, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container can holds composition including the IL-17 antibody and may have a sterile access port. The label on, or associated with, the container may indicate that the composition is used for treating CSU. The article kit may further include a second container comprising a pharmaceutically-acceptable buffer, such as phosphate -buffered saline, Ringer's solution and dextrose solution. The kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

According to some embodiments, there is provided a kit which includes: (a) one or more dosages ranging from about 1 mg to about 500 mg of an anti-IL-17 antibody (or an antigen binding portion thereof) that binds and affects (such as, inhibits) IL-17 activity; and (b) instructions for using the anti-IL-17 antibody for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence or severity of CSU or at least one symptom associated with CSU in a subject in a need thereof, wherein the instructions include instructions to administer the anti- IL-17 antibody at least two times. In some embodiments, a change or reduction in UAS or UAS7 over time is indicative of amelioration in disease condition. In some embodiments, the one or more dosages of the anti-IL-17 antibody in the kit may range from about 100 mg to about 300 mg. In some embodiments, the one or more dosages of the anti-IL-17 antibody may be about 150 mg. According to some embodiments, the kit may include multiple dosages which may be the same or different from one another. In some embodiments, the IL-17 antibody is included in a pharmaceutical composition which may further include one or more pharmaceutically acceptable carriers. According to some embodiments, the anti- IL-17 antibody may be administered at a dose ranging from at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight. According to some embodiments, the anti- IL-17 antibody may be administered at a dose ranging from at least about 1 mg/kg to at least about 3 mg/kg body weight. According to some embodiments, the anti- IL-17 antibody may be administered once about every 1, 2, 3, and/or 4 weeks. According to some embodiments, the anti-IL-17 antibody may be administered once about every 1, 2, 3, 4, 5, 6 months or more. According to some embodiments, the anti- IL-17 antibody may be administered once about every 1-2 weeks for about 4-8 weeks and then once about every 2 weeks - 3 months for about 6-12 months or more. According to some embodiments, the anti- IL-17 antibody may be administered once about every week for about four weeks and then once about every two weeks for about six months or more.

According to some embodiments, there is further provided a method for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence or severity of CSU or at least one symptom associated with CSU in a subject in a need thereof, the method includes administering to the subject a therapeutically effective amount of an agent capable of interfering with, inhibiting and/or preventing IL-17 - IL-17receptor (IL-17r) interaction and a pharmaceutically acceptable carrier. In some embodiments, the agent capable of interfering with, inhibiting and/or preventing IL-17 - IL-17r interaction may include an anti-IL-17 antibody, or antigen-binding fragment thereof. In some embodiments, the agent capable of interfering with, inhibiting and/or preventing IL-17 - IL-17r interaction may include an anti-IL-17r antibody, or antigen-binding fragment thereof. In some embodiments, the agent may be administered systemically. In some embodiments, the agent may be administered at least twice.

According to some embodiments, there is provided herein a pharmaceutical composition for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence or severity of Chronic spontaneous urticaria (CSU) or at least one symptom associated with CSU in a subject in a need thereof, the pharmaceutical composition includes a therapeutically effective amount of an agent capable of interfering with, inhibiting and/or preventing IL-17 - IL-17r interaction and a pharmaceutically acceptable carrier. In some embodiment’s, the pharmaceutical composition may be administered systemically. In some embodiments, the pharmaceutical composition may be administered at least twice. According to some embodiments, there is further provided herein a kit which may include: (a) an agent capable of interfering with, inhibiting and/or preventing IL-17 - IL- 17receptor (IL-17r) interaction and a pharmaceutically acceptable carrier; and (b) instructions for using the anti-IL-17 antibody for treating, preventing, inhibiting, ameliorating and/or reducing the occurrence or severity of CSU or at least one symptom associated with CSU in a subject in a need thereof. In some embodiments, the agent capable of interfering with, inhibiting and/or preventing IL-17 - IL-17r interaction may be an anti-IL-17 antibody, or antigen-binding fragment thereof. In some embodiments, the agent capable of interfering with, inhibiting and/or preventing IL-17 - IL-17r interaction may be an anti-IL-17r antibody, or antigen-binding fragment thereof. In some embodiments, the agent may be administered systemically. In some embodiments, the agent may be administered at least twice.

In the description and claims of the application, the words“include” and“have”, and forms thereof, are not limited to members in a list with which the words may be associated.

As used herein, the term“about” may be used to specify a value of a quantity or parameter (e.g. the length of an element) to within a continuous range of values in the neighborhood of (and including) a given (stated) value. According to some embodiments, “about” may specify the value of a parameter to be between 80 % and 120 % of the given value. For example, the statement“the length of the element is equal to about 1 m” is equivalent to the statement “the length of the element is between 0.8 m and 1.2 m”. According to some embodiments,“about” may specify the value of a parameter to be between 90 % and 110 % of the given value. According to some embodiments,“about” may specify the value of a parameter to be between 95 % and 105 % of the given value.

It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination or as suitable in any other described embodiment of the disclosure. No feature described in the context of an embodiment is to be considered an essential feature of that embodiment, unless explicitly specified as such. Although steps of methods according to some embodiments may be described in a specific sequence, methods of the disclosure may include some or all of the described steps carried out in a different order. A method of the disclosure may include a few of the steps described or all of the steps described. No particular step in a disclosed method is to be considered an essential step of that method, unless explicitly specified as such.

Although the disclosure is described in conjunction with specific embodiments thereof, it is evident that numerous alternatives, modifications and variations that are apparent to those skilled in the art may exist. Accordingly, the disclosure embraces all such alternatives, modifications and variations that fall within the scope of the appended claims. It is to be understood that the disclosure is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth herein. Other embodiments may be practiced, and an embodiment may be carried out in various ways.

The phraseology and terminology employed herein are for descriptive purpose and should not be regarded as limiting. Citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the disclosure. Section headings are used herein to ease understanding of the specification and should not be construed as necessarily limiting.

While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced be interpreted to include all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope.

The following examples are presented in order to more fully illustrate certain embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention. EXAMPLES

Materials and Methods:

Patients

The study described herein included 30 patients with severe CSU treated at the Urticaria Centers of Reference and Excellence (UCARE) of Charite, Universitatsmedizin Berlin, Germany, and the Division of Allergy & Clinical Immunology of the Bnai-Zion Medical Center, Haifa, Israel, and the Department of Dermatology at the Sheba Medical Center, Tel-Aviv, Israel. All enrolled patients suffered from long lasting and severe CSU. Skin biopsies from these patients were evaluated for the expression of: CD4+T cells, mast cells and IL-17. Eight additional patients, who were refractory to multiple therapies including, omalizumab and cyclosporine A, were treated with anti-IL-17 (Secukinumab), as detailed below. The study was approved by the local Helsinki committee and patients signed on informed consent prior to the first administration of the antibody.

Skin immunohistochemistry

Lesional (n=20) and non lesional (n=10) skin biopsies of 30 CSU patients as well as control skin biopsies from 10 healthy subjects were evaluated for the expression of CD4+ T cells, mast cells and IL-17. Briefly, formalin-fixed paraffin-embedded skin tissue sections were serially sliced into 5 pm slices by a microtome. The slides were deparaffinized by xylene and then rehydrated by absolute ethanol, 96% ethanol, 70% ethanol and two quick distilled water washes. The antigen retrieval was done by cooker pressure in an EDTA solution (2mM, and pH- 8.0). H2O2 3% in methanol was used to block endogenous hydrogen peroxidase. In order to block non-specific endogenous biotin, a commercial biotin blocker was used, according to manufacturer’s instructions. Primary antibody, Rabbit polyclonal anti human- IL-17 (1 : 100, Proteintech group LTD, Rosemont, IL, USA), Rabbit polyclonal anti-human cKit (Abeam, Cambridge, USA) (1: 100), and rabbit polyclonal anti-human CD4 (Abeam) (1:300) were incubated with the slides. Secondary antibody and staining were performed by using the commercial“Histostain+” kit, ("Invitrogen", Camarillo, CA, USA), according to manufacturer’s instructions. The immuno-histochemical staining was evaluated by two independent pathologists and was inspected for localization and staining intensity. The extent of staining was given a score from 0-3 (0-absent and 3 for strong). The amount of CD4+cells and cKit (CD 117+ cells) in all skin biopsies was quantified by using IMARIS microscope software. Using this method of quantification, the whole slide was scanned and quantified for the amount of CD4+ and cKit+ cells in all available slides.

Statistical analysis

Statistical analysis was performed using Graph Pad Prism software. The comparison of the differences between two groups was performed using the unpaired two tailed student t-test, whereas for more than two groups it was done by using ANOVA test. Statistical Significance was considered with a P-value of 0.05 or less (p-value < 0.05).

Treatment with anti-IL-17 antibody

An antibody against IL-17a (Anti-IL-17a, (Secukinumab, Novartis) was administered to eight (8) patients with CSU, who had high disease activity (UAS7 32-40) during the whole period prior to treatment. These patients were refractory to several treatments including omalizumab (up to 450 mg\4 weeks) and cyclosporine A. At the time of the start of anti-IL-17 treatment, these patients were on long term oral steroid therapy combined with high off-label doses of anti -histamines. Anti-IL-17 (Secukinumab) was administered sub-cutaneously (s.c.) at 150 mg every week for four consecutive weeks and then 150 mg every two weeks. This treatment was continued for 6 months. The treatment response was measured by looking for the reduction of UAS7 from baseline (i.e. starting point prior to treatment), at one-week interval for the first month and then every two weeks.

Example 1: Comparison of skin biopsies of healthy subjects and CSU subjects

Skin biopsies were obtained and stained as described above.

Inspection of the biopsies of the CSU patients identified rich infiltrates of lymphocytes and mast cells attached close to each other. This is in contrast to normal skin biopsies, where immune cells, namely lymphocytes, were scarce. All biopsy slides were analyzed and the number of cells (CD4+ T or mast cells) in all of them is presented as the mean ± SD. CD4+T cells in skin biopsies

Biopsies from CUS patients and healthy control were obtained and stained for identification of CD4+T cells. In CSU biopsies, CD4+T cells were found to be significantly much more abundant compared to biopsies from healthy subjects (mean 50±6 cells\slide in CSU biopsies, compared to mean 7± 2 cells\slide in healthy subject biopsies, as shown in the bar graph presented in Fig. 1C, p<0.0002). Fig. 1A shows exemplary biopsies from healthy subjects and Fig. IB shows biopsies from CSU subjects, whereby abundancy of stained cells were similar in both lesional and non lesional CSU skin regions. Arrows mark positive CD4 cells in skin biopsies).

CD117+ (cKit) mast cells in skin biopsies

Biopsies from CUS patients and healthy control were obtained and stained for identification of CD177+ (cKit) mast cells. In CSU skin biopsies, CD117+ mast cells were vastly increased in both lesional and non lesional skin regions (mean 200±20 cells\slide in CSU biopsies, compared to biopsies from healthy subjects (mean 40±10 cells\slide), as shown in the bar graph presented in Fig. 2C, p=0.0099). Fig. 2B shows stained cells in biopsies of CSU subjects Fig. 2A shows stained cells in biopsies of healthy subjects.

Biopsies from CUS patients and healthy control were obtained and stained for identification of IL-17 expressions. In skin biopsies of healthy subjects, IL-17 staining was almost negative (score 0-1), as shown in Fig. 3 A. However, as can be sees in Figs. 3B and 3C, a strong positive staining of IL-17 (score 2-3) was demonstrated in skin biopsies taken from severe CSU patients, and was further found to be similar in both lesional and non-lesional skin biopsies. In Fig. 3B, arrows denote positive staining of endothelial cells and infiltrating lymphocytes (X20 magnification).

Fig. 3C demonstrates positive staining of endothelial cells and lymphocytes in X40 magnification. Reference is now made to Fig. 4A and 4B, which depicts positive IL-17 stained cells in CSU skin biopsies. Positive staining was noticed mainly in CD4+ lymphocytes, endothelial cells and mast cells. Most IL-17 expressing CD4+ T cells and IL-17 positive mast cells were noticed to be positioned in proximity to each other. In Figure 4A, Arrow No. l denotes a mast cell in proximity to positive stained CD4 lymphocytes (Arrows No. 2) at X200 magnification. In Figure 4B, positive IL-17 stained mast cell in CSU skin biopsy are noticed (Arrow No. 3), endothelial cells (Arrow No. 4) and lymphocytes (arrows No. 4 and 5) at X400 magnification.

Example 2: Effect of administration of IL-17 antibody to CSU patients on disease severity

CSU patients were administered s.c. with 300 mg of Secukinumab once a week for four consecutive weeks and thereafter, every two weeks. Significant side effects were reported (including, inter alia, fever, muscle aches and fatigue).

As detailed above, eight CSU patients were administered s.c. with 150 mg of Secukinumab (Cosen tyx) once a week for four consecutive weeks and thereafter, 150 mg every two weeks. No adverse side effects were reported, not systemic side effects and nor local side effects (at the site of injection).

Improvement in disease symptoms was noticed following the first 2-3 weekly administrations. The improvement included improvements in pruritus and urticarial rash, a reduction of UAS7 to equal or below 20 in all treated subjects and improvement in the angioedema severity.

Additionally, Cyclosporine A and steroids administration were fully ceased following the first two injections. Anti-histamines were also reduced following 2-3 injections.

Additionally, reduced angioedema was noticed following 5-6 weeks of treatment. By week 8 of treatment, significant improvement of all symptoms (UAS7 below 6-8) was noticed. All patients were maintained on Secukinumab administration, while remaining free of all other therapies.

The results are presented in Table 1 below, which summarizes the UAS7 of patients before and after treatment: Table 1- UAS7 score before and after treatment

Advantageously, and as can be seen from the results presented in Table 1 and Fig. 5, the treatment caused a significant reduction in UAS7 (Urticaria Activity Score Over 7 Days) values after treatment (at 30 days and 90 days), and the treatment caused a significant remission for as long as the patient were maintained on the treatment regimen.

Reference is made to Figs. 6A-6F, which show pictograms of patient's skin from various body parts (back, knee and underarm), prior to treatment (Figs. 6A, 6C and 6E) and after treatment with anti IL-17 for 30-60 days (Fig. 6B, 6D and 6F, respectively). The results clearly show the immense effect of the treatment on the improvement in pruritus and urticarial rash. In addition, patients reported an improvement in quality of life.

The results demonstrate that anti-IL-17 agents can be used as a safe and highly effective therapy for CSU, which is further of steroid sparing effect.

Example 3: Effect of administration of a combination therapy of IL-17 antibody and omalizumab on disease severity of CSU patients

In some cases, a combined treatment of anti-IL-17 with omalizumab may be beneficial when omalizumab treatment alone fails. To this aim, a cohort of CSU patients are administered with anti- 17 antibody (such as

Secukinumab) alternatively to omalizumab, once a week for four consecutive weeks and thereafter, every two weeks for additional 6 months.

Disease severity was determined by one or more of the parameters of: pruritus and urticarial rash, UAS7 score, angioedema severity and quality of life.

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