METHODS AND TREATMENT FOR MULTIPLE MYELOMA INVOLVING ANTIBODIES TO IL- 18

[0001] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December 6, 2021, is named 01118-0050-00PCT_ST25.txt and is 109,047 bytes in size.

FIELD OF THE INVENTION

[0002] The present disclosure relates to methods of treating subjects with active relapsed/refractory (R/R) multiple myeloma (MM) by administering an anti -interleukin 18 (IL-18) antibody.

BACKGROUND OF THE INVENTION

[0003] Multiple myeloma mostly occurs in older adults. The median age at diagnosis is 66 years; only 10% of patients are younger than 50 years and 2% of patients are younger than 40 years. (Blade, J & Kyle, RA, Leuk. Lymphoma 30:493 (1998)). The disease accounts for approximately 1% to 2% of all cancers and slightly more than 17% of hematologic malignancies in the US. (Siegel, RL Miller, KD, & Jemal, A, CA, Cancer J Clin 69:7 (2019)). The annual incidence in the US is approximately 4 to 5 per 100,000. (Kyle, RA et al., Cancer 101:2667 (2004)). Worldwide, there are approximately 160,000 cases and 106,000 deaths per year attributed to MM. (Cowan, AJ et al., JAMA Oncol 4:1221 (2018); Bray, F, et al., CA Cancer J Clin 68:394 (2018)).

[0004] Multiple myeloma occurs in all races and all geographic locations. (Cowan, AJ et al., JAMA Oncol 4:1221 (2018); Bray, F, et al., CA Cancer J Clin 68:394 (2018)). The incidence varies by ethnicity; the incidence in African Americans and Blacks from Africa is two to three times that in Caucasians. (Kyle, RA, et al., Mayo Clin Proc 78:21 (2003); Waxman, AJ, et al. Blood 116:5501 (2010), Shirley, MH, et al., Br J Haematol 163:465 (2013)). In contrast, the risk is lower in Asians from Japan and in Mexicans (Shirley, MH, et al., Br J Haematol 163:465 (2013); Huang, SY, et al., Cancer 110:896 (2007). Multiple myeloma is also slightly more frequent in men than in women (approximately 1.4:1). (Bray, F, et al., CA Cancer J Clin 68:394 (2018)). The risk of developing MM increases with body mass index. (Kyrgiou, M, et al., BMJ 356; j477 (2017); Islami, F, et al., JAMA Oncol 5:384 (2019)). Multiple myeloma is characterized by the neoplastic proliferation of plasma cells that produce a monoclonal immunoglobulin. (Kariyawasan, CC, et al., QJM 100:635 (2007)). The plasma cells proliferate in the bone marrow and often cause skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. Multiple myeloma often presents with one more of the following: bone pain with lytic lesions discovered on routine skeletal films or other imaging modalities; an increased total serum protein concentration and/or the presence of a monoclonal protein in the urine or serum; unexplained anemia; hypercalcemia, which is either symptomatic or discovered incidentally; and acute renal insufficiency/failure due to concurrent immunoglobulin light chain (AL) amyloidosis. The bone marrow of the vast majority of patients contains 10% or more clonal plasma cells, but ranges from less than 5% to almost 100%, with a median value of 50%. (Lauby-Secretan, B, et al., NEJM 375(8):794-798 (2016)).

[0005] Increased levels of IL- 18 have been associated with decreased survival in patients with MM. One group of researchers measured serum levels of IL-18, vascular endothelial growth factor (VEGF), angiogenin, TNF-alpha, and CRP in 65 newly diagnosed myeloma patients. (Alexandrakis, MG, et al., Leukemia Research 28(3):259-266 (2004)). In the study, results showed that IL-18, VEGF, angiogenin, TNF-alpha and CRP were significantly higher at stage III in comparison to stages II and I. These cytokines (measured in 27 patients) significantly decreased after treatment. In survival analysis, higher levels of IL- 18 were associated with a poorer prognosis. The researchers concluded that increased serum IL- 18 in myeloma patients correlates with advanced disease, increased levels of angiogenic cytokines, and worse survival.

[0006] A recent study demonstrated that the pro-inflammatory cytokine IL- 18 is critically involved in both proinflammatory disease progression and interference with immunodestruction of MM. (Nakamura K, et al., Cancer Cell 33:634-648 (2018)). In this study, high levels of bone marrow plasma IL- 18 were associated with poor overall survival in MM patients.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1. Serum concentrations of Antibody A in human subjects with R/R MM in cohorts 1 and 2. The Y-axis is Antibody A concentration in pg/mL. Each line refers to data from one patient. Each patient is also assigned a number. Patients 005-0001 and 005- 0003 were dosed on Cycle 1 (Day 1) and Cycle 2 (Day 1). The total amount of drug given to the patient per dose based on the patient’s weight is shown in parentheses behind each patient’s number. [0008] Figure 2. Serum concentrations of IL- 18 in human subjects with R/R MM treated with Antibody A. The Y-axis is IL- 18 in pg/mL. Each line refers to data from one patient. Each patient is also assigned a number. Patients 005-0001 and 005-0003 were dosed on Cycle 1 (Day 1) and Cycle 2 (Day 1) (Day 29). “LLOQ” refers to lowest limit of quantitation. LLOQ = 79 pg/mL for Patient 005-0001 and 54 pg/mL for all other patients. Samples <LLOQ reported as LLOQ (LLOQs indicated by dotted line). The total amount of drug given to the patient per dose based on the patient’s weight is shown in parentheses behind each patient’s number.

[0009] Figure 3. Serum concentrations of IL- 18 binding protein in human subjects with R/R MM treated with Antibody A. The Y-axis is IL-18bp (ng/mL). Each line refers to data from one patient. Each patient is also assigned a number. Patients 005-0001 and 005- 0003 were dosed on Cycle 1 (Day 1) and Cycle 2 (Day 1) (Day 29). The total amount of drug given to the patient per dose based on the patient’s weight is shown in parentheses behind each patient’s number.

SUMMARY

[0010] The present disclosure includes, for example, any one or a combination of the following embodiments:

Embodiment 1. A method of treating active relapsed/refractory (R/R) multiple myeloma, comprising administering to a human subject diagnosed with multiple myeloma an effective amount of an anti-IL-18 antibody wherein the anti-IL-18 antibody comprises the following six CDRs:

(a) a HCDR1 having an amino acid sequence of SEQ ID NO: 122;

(b) a HCDR2 having an amino acid sequence of SEQ ID NO: 123;

(c) a HCDR3 having an amino acid sequence of SEQ ID NO: 124;

(d) a LCDR1 having an amino acid sequence of SEQ ID NO: 126;

(e) a LCDR2 having an amino acid sequence of SEQ ID NO: 127; and

(1) a LCDR3 having an amino acid sequence of SEQ ID NO: 128; and i) wherein the subject has active multiple myeloma despite prior therapy with a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; and/or ii) wherein the subject has measurable myeloma based on any of the following: (a) serum M-protein greater than 0.5 g/dL;

(b) urine M-protein greater than 200 mg/24 hours;

(c) serum free light chains greater than 10 mg/dL; and

(d) measurable plasmacytoma or extramedullary disease; and/or iii) wherein the subject has an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; and/or iv) wherein the subject has undergone prior autologous hematopoietic stem cell transplantation more than 100 days prior to a screening visit.

Embodiment 2. The method of embodiment 1, wherein the subject is not administered an immunomodulatory drug at the same time as the anti-IL-18 antibody.

Embodiment 3. The method of embodiment 2, wherein the immunomodulatory drug is selected from systemic glucocorticoids, anti-TNFa antibodies, anti-IL-17 antibodies, anti-IL-12/23 antibodies, PDE-4 inhibitors, JAK inhibitors, IL-6 inhibitors, rituximab, methotrexate, cyclosporine, and my cophenolate.

Embodiment 4. The method of any one of embodiments 1-3, wherein the subject has elevated free or total serum or bone marrow IL- 18 levels.

Embodiment 5. The method of any one of embodiments 1-4, wherein the level of serum or bone marrow IL- 18 is measured prior to administration of the anti-IL-18 antibody.

Embodiment 6. The method of any one of embodiments 1-5, wherein the level of serum or bone marrow IL- 18 is measured after administration of the anti-IL-18 antibody, optionally as a marker for effectiveness of treatment.

Embodiment 7. The method of any one of embodiments 1-6, wherein the level of serum or bone marrow IL- 18 is elevated as compared to levels in a subject without active R/R multiple myeloma or as compared to a negative control.

Embodiment 8. The method of any one of embodiments 1-7, wherein the level of serum or bone marrow IL-18 is free IL-18, optionally wherein the level of free IL-18 is calculated.

Embodiment 9. The method of any one of embodiments 1-7, wherein the level of serum or bone marrow IL- 18 is total IL- 18.

Embodiment 10. The method of any one of embodiments 1-8, wherein the subject has elevated free IL-18.

Embodiment 11. The method of any one of embodiments 1-7 or 10, wherein the subject has elevated total IL- 18. Embodiment 12. A method of treating active relapsed/ refractory (R/R) multiple myeloma, comprising administering to a human subject diagnosed with multiple myeloma an effective amount of an anti-IL-18 antibody and wherein the subject has elevated free or total IL-18 levels in the serum or bone marrow compared to a subject without active R/R multiple myeloma or as compared to a negative control, wherein the anti-IL-18 antibody comprises the following six CDRs:

(a) a HCDR1 having an amino acid sequence of SEQ ID NO: 122;

(b) a HCDR2 having an amino acid sequence of SEQ ID NO: 123;

(c) a HCDR3 having an amino acid sequence of SEQ ID NO: 124;

(d) a LCDR1 having an amino acid sequence of SEQ ID NO: 126;

(e) a LCDR2 having an amino acid sequence of SEQ ID NO: 127; and

(f) a LCDR3 having an amino acid sequence of SEQ ID NO: 128; and optionally a) wherein the subject has active multiple myeloma despite prior therapy with a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; and/or b) wherein the subject has measurable myeloma based on any of the following:

(a) serum M-protein greater than 0.5 g/dL;

(b) urine M-protein greater than 200 mg/24 hours;

(c) serum free light chains greater than 10 mg/dL; and

(d) measurable plasmacytoma or extramedullary disease; and/or c) wherein the subject has an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; and/or d) wherein the subject has undergone prior autologous hematopoietic stem cell transplantation more than 100 days prior to a screening visit.

Embodiment 13. The method of embodiment 12, wherein the level of serum or bone marrow IL- 18 is measured prior to administration of the anti-IL-18 antibody.

Embodiment 14. The method of embodiment 12 or 13, wherein the level of serum or bone marrow IL- 18 is measured after administration of the anti-IL-18 antibody, optionally as a marker for effectiveness of treatment.

Embodiment 15. The method of any one of embodiments 12-14, wherein the level of serum or bone marrow free or total IL- 18 is elevated as compared to levels in a subject without active R/R multiple myeloma. Embodiment 16. The method of any one of embodiments 12-14, wherein the level of serum or bone marrow IL-18 is free IL-18, optionally wherein the level of free IL-18 is calculated.

Embodiment 17. The method of any one of embodiments 12-14, wherein the level of serum or bone marrow IL- 18 is total IL- 18.

Embodiment 18. The method of any one of embodiments 1-17, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence that is at least 90% identical to the full sequence of SEQ ID NO: 121.

Embodiment 19. The method of any one of embodiments 1-18, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence that is identical to the full sequence of SEQ ID NO: 121.

Embodiment 20. The method of any one of embodiments 1-19, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence that is at least 90% identical to the full sequence of SEQ ID NO: 125.

Embodiment 21. The method of any one of embodiments 1-20, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence that is identical to the full sequence of SEQ ID NO: 125.

Embodiment 22. The method of any one of embodiments 1-21, wherein the anti-IL-18 antibody comprises an antibody VH domain and an antibody VL domain, wherein the amino acid sequence of the antibody VH domain is at least 90% identical to the full sequence of SEQ ID NO: 121, and the antibody VL domain is at least 90% identical to the full sequence of SEQ ID NO: 125.

Embodiment 23. The method of any one of embodiments 1-22, wherein the anti-IL-18 antibody is administered in the form of a pharmaceutically acceptable composition.

Embodiment 24. The method of any one of embodiments 1-23, wherein the anti-IL-18 antibody is administered for at least two 28-day treatment cycles, wherein the anti-IL- 18 antibody is administered on day 1 of each 28-day treatment cycle.

Embodiment 25. The method of any one of embodiments 1-24, comprising administering the anti-IL-18 antibody to the subject at a dose of 10, 30, 100, 300, or 1000 mg.

Embodiment 26. The method of any one of embodiments 1-24, comprising administering the anti-IL-18 antibody to the subject at a dose of 10 to 30 mg/kg. Embodiment 27. The method of any one of embodiments 1-26, comprising administering the anti-IL-18 antibody to the subject at a dose of 0.03, 0.1, or 0.3 mg/kg.

Embodiment 28. The method of any one of embodiments 1-27, comprising administering the anti-IL18 antibody to the subject at a dose of 0.01 mg/kg to 36 mg/kg.

Embodiment 29. The method of any one of embodiments 1-28, comprising administering the anti-IL-18 antibody to the subject at a dose of 4 mg/kg, or 9 mg/kg, or 14 mg/kg.

Embodiment 30. The method of any one of embodiments 1-29, wherein the anti-IL-18 antibody is administered intravenously.

Embodiment 31. The method of any one of embodiments 1-30, wherein the anti-IL-18 antibody is administered subcutaneously.

Embodiment 32. The method of any one of embodiments 1-31, wherein the anti-IL-18 antibody is administered once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.

Embodiment 33. The method of any one of embodiments 1-32, wherein the anti-IL-18 antibody is administered on day 1 in 28-day treatment cycles.

Embodiment 34. The method of any one of embodiments 1-33, comprising administering the anti-IL-18 antibody to the subject at a dose of 4 mg/kg on day 1 in 28-day treatment cycles, at a dose of 9 mg/kg on day 1 in 28-day treatment cycles, or at a dose of 14 mg/kg on day 1 in 28-day treatment cycles.

Embodiment 35. The method of any one of embodiments 1-34, wherein the subject is 18 years of age or older.

Embodiment 36. The method of any one of embodiments 1-35, wherein treatment with the anti-IL-18 antibody shortens time to response (TTR) compared to standard-of-care therapy.

Embodiment 37. The method of any one of embodiments 1-36, wherein treatment with the anti-IL-18 antibody extends progression-free survival (PFS) compared to standard-of-care therapy.

Embodiment 38. The method of any one of embodiments 1-37, wherein treatment with the anti -IL-18 antibody extends duration of response (DOR) compared to standard-of- care therapy. Embodiment 39. The method of any one of embodiments 1-38, wherein the subject achieves a stringent complete response (sCR) according to International Myeloma Working Group (IMWG) response criteria after two or more 28-day treatment cycles.

Embodiment 40. The method of any one of embodiments 1-39, wherein the subject achieves a complete response (CR) according to IMWG response criteria after two or more 28-day treatment cycles.

Embodiment 41. The method of any one of embodiments 1-40, wherein the subject achieves a very good partial response (VGPR) according to IMWG response criteria after two or more 28-day treatment cycles.

Embodiment 42. The method of any one of embodiments 1-41, wherein the subject achieves a partial response (PR) according to IMWG response criteria after two or more 28-day treatment cycles.

Embodiment 43. The method of any one of embodiments 1-42, wherein there is a greater than or equal to 90% reduction in the subject’s serum M-protein as measured by SPEP after one or administrations of the anti-IL-18 antibody.

Embodiment 44. The method of any one of embodiments 1-42, wherein there is a greater than or equal to 50% reduction in the subject’s serum M-protein as measured by SPEP after one or more administrations of the anti-IL-18 antibody.

Embodiment 45. The method of any one of embodiments 1-42, wherein there is a greater than or equal to 25% reduction in the subject’s serum M protein as measured by SPEP after one or more administrations of the anti-IL-18 antibody, and wherein there is a less than or equal to 49% reduction in the subject’s serum M-protein as measured by SPEP after one or more administrations of the anti -IL-18 antibody.

Embodiment 46. The method of any one of embodiments 1-42, wherein there is a reduction in the subject’s serum M-protein as measured by SPEP after one or more administrations of the anti-IL-18 antibody.

Embodiment 47. The method of any one of embodiments 1-46, wherein the subject’s M- protein as measured by SPEP stabilizes after one or administrations of the anti-IL-18 antibody.

Embodiment 48. The method of any one of embodiments 1-47, wherein the subject achieves an improved Eastern Cooperative Oncology Group Performance Status (ECOG PS) score. Embodiment 49. The method of any one of embodiments 1-48, wherein the subject has undetectable levels of serum or bone marrow free or total IL- 18 at about 28 days after administration of the anti -IL- 18 antibody.

Embodiment 50. The method of any one of embodiments 1-49, wherein the subject has undetectable levels of serum or bone marrow free IL- 18 at about 28 days after administration of the anti -IL- 18 antibody.

Embodiment 51. The method of any one of embodiments 1-50, wherein the subject has undetectable levels of serum or bone marrow free or total IL- 18 at about 112 days after administration of the first dose of the anti -IL-18 antibody.

Embodiment 52. The method of any one of embodiments 1-50, wherein the subject has undetectable levels of serum free IL- 18 at about 112 days after administration of the anti-IL-18 antibody.

Embodiment 53. The method of any one of embodiments 1-50, wherein the subject has reduced levels of serum or bone marrow free or total IL- 18 at about 28 days after administration of the anti -IL- 18 antibody.

Embodiment 54. The method any one of embodiments 1-50, wherein the subject has reduced levels of serum or bone marrow free IL-18 at about 112 days after administration of the anti -IL- 18 antibody

Embodiment 55. A kit for use in a method of any one of embodiments 1-54 comprising an anti-IL-18 antibody and reagents for carrying out the method, optionally wherein the antibody comprises the following six CDRs:

(a) a HCDR1 having an amino acid sequence of SEQ ID NO: 122;

(b) a HCDR2 having an amino acid sequence of SEQ ID NO: 123;

(c) a HCDR3 having an amino acid sequence of SEQ ID NO: 124;

(d) a LCDR1 having an amino acid sequence of SEQ ID NO: 126;

(e) a LCDR2 having an amino acid sequence of SEQ ID NO: 127; and

(f) a LCDR3 having an amino acid sequence of SEQ ID NO: 128; and/or wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence that is at least 90% identical to the full sequence of SEQ ID NO: 121, and a VL domain having an amino acid sequence that is at least 90% identical to the full sequence of SEQ ID NO: 125. DETAILED DESCRIPTION OF THE INVENTION

[0011] The following definitions are provided to facilitate an understanding of the invention. They are not intended to limit the invention in any way.

Definitions

[0012] For purposes of the present invention, “a” or “an” entity refers to one or more of that entity; for example, “a cDNA” refers to one or more cDNA or at least one cDNA. As such, the terms “a” or “an,” “one or more” and “at least one” can be used interchangeably herein. It is also noted that the terms “comprising,” “including,” and “having” can be used interchangeably. Furthermore, a compound “selected from the group consisting of’ refers to one or more of the compounds in the list that follows, including mixtures (i.e. , combinations) of two or more of the compounds. According to the present invention, an “isolated,” or “biologically pure” molecule is a compound that has been removed from its natural milieu. As such, the terms “isolated” and “biologically pure” do not necessarily reflect the extent to which the compound has been purified. An isolated compound of the present invention can be obtained from its natural source, can be produced using laboratory synthetic techniques or can be produced by any such chemical synthetic route.

[0013] “IL-18” or “Interleukin- 18” or “interferon-gamma inducing factor” or “IFN-y- inducing factor” refers to a proinflammatory cytokine encoded by the IL 18 gene that belongs to the IL-1 family of cytokines. Similar to IL-ip, it is synthesized as an inactive precursor called pro-IL-18 that is activated by cleavage by caspase-1. Pro-IL-18 is present in healthy cells and constitutively expressed by monocytes and epithelial cells. IL-18 has roles in stimulating both adaptive and innate immune response.

[0014] “Elevated IL-18” as used herein refers to a level of total IL-18 detected in a subject that is higher than a normal control. The normal control can be determined by those of skill in the art as applicable to the particular situation. In some instances, the normal control is an industry standard agreed upon by those of skill as being a level or range of levels that is typical of an individual without a IL-18-associated condition. In some instances, the normal control is a reference level of IL- 18 from the same individual taken at a time point, and whether the subject has elevated IL- 18 is determined based on a sample from that same individual taken at a different, typically later, time point.

[0015] “Free IL-18” or “free (active) IL-18” herein refers to non-bound form IL-18, which is the active form of IL-18. In humans, free IL-18 is neutralized (inactivated) by IL- 18BP, which binds IL-18 and inhibits its activity by interfering with its interaction with IL- 18Ra. Free IL- 18 may be calculated according to known methods, e.g., Palladino et al. (2012) J. Neuroinflammation 9(206).

[0016] “Bound IL-18,” or the like, refers to IL-18 that is bound to a natural ligand, optionally wherein the natural ligand is IL-18Ra or IL-18BP.

[0017] “Total IL- 18,” or the like, refers to the total amount of free IL- 18 and bound

IL-18.

[0018] “Serum” or “circulating” IL- 18 is IL- 18 that is located in the serum.

[0019] “Bone marrow” IL- 18 is IL- 18 that is located in the bone marrow.

[0020] “Undetectable levels of serum IL- 18” refers to levels of IL- 18 that are below the level of quantification of an assay for measuring IL-18.

[0021] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity. As used herein, the term refers to a molecule comprising at least complementarity-determining region (CDR) 1, CDR2, and CDR3 of a heavy chain and at least CDR1, CDR2, and CDR3 of a light chain, wherein the molecule is capable of binding to antigen. As described herein, a “set of CDRs” comprises CDR1, CDR2 and CDR3. Thus, a set of HCDRs refers to HCDR1, HCDR2 and HCDR3, and a set of LCDRs refers to LCDR1, LCDR2 and LCDR3. Unless otherwise stated, a “set of CDRs” includes HCDRs and LCDRs. The term antibody includes, but is not limited to, fragments that are capable of binding antigen, such as Fv, single-chain Fv (scFv), Fab, Fab’, and (Fab’)2. The term antibody also includes, but is not limited to, chimeric antibodies, humanized antibodies, human antibodies, and antibodies of various species such as mouse, cynomolgus monkey, etc.

[0022] The term “heavy chain” refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term “full-length heavy chain” refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0023] The term “heavy chain variable region” or “VH domain” refers to a region comprising a heavy chain complementarity determining region (CDR) 1, framework region (FR) 2, CDR2, FR3, and CDR3 of the heavy chain. In some embodiments, a heavy chain variable region also comprises at least a portion of an FR1 and/or at least a portion of an FR4. In some embodiments, a heavy chain CDR1 corresponds to Kabat residues 31 to 35; a heavy chain CDR2 corresponds to Kabat residues 50 to 65; and a heavy chain CDR3 corresponds to Kabat residues 95 to 102. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.).

[0024] The term “light chain” refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term “full-length light chain” refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0025] The term “light chain variable region” or “VL domain” refers to a region comprising a light chain CDR1, FR2, HVR2, FR3, and HVR3. In some embodiments, a light chain variable region also comprises an FR1 and/or an FR4. In some embodiments, a light chain CDR1 corresponds to Kabat residues 24 to 34; a light chain CDR2 corresponds to Kabat residues 50 to 56; and a light chain CDR3 corresponds to Kabat residues 89 to 97. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.).

[0026] A “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. In some embodiments, a chimeric antibody refers to an antibody comprising at least one variable region from a first species (such as mouse, rat, cynomolgus monkey, etc.) and at least one constant region from a second species (such as human, cynomolgus monkey, etc.). In some embodiments, a chimeric antibody comprises at least one mouse variable region and at least one human constant region. In some embodiments, a chimeric antibody comprises at least one cynomolgus variable region and at least one human constant region. In some embodiments, all of the variable regions of a chimeric antibody are from a first species and all of the constant regions of the chimeric antibody are from a second species.

[0027] A “humanized antibody” refers to an antibody in which at least one amino acid in a framework region of a non-human variable region has been replaced with the corresponding amino acid from a human variable region. In some embodiments, a humanized antibody comprises at least one human constant region or fragment thereof. In some embodiments, a humanized antibody is an Fab, an scFv, a (Fab')2, etc.

[0028] A “human antibody” as used herein refers to antibodies produced in humans, antibodies produced in non-human animals that comprise human immunoglobulin genes, such as XenoMouse®, and antibodies selected using in vitro methods, such as phage display, wherein the antibody repertoire is based on a human immunoglobulin sequences.

[0029] The term “leader sequence” refers to a sequence of amino acid residues located at the N terminus of a polypeptide that facilitates secretion of a polypeptide from a mammalian cell. A leader sequence may be cleaved upon export of the polypeptide from the mammalian cell, forming a mature protein. Leader sequences may be natural or synthetic, and they may be heterologous or homologous to the protein to which they are attached.

[0030] “Percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0031] The terms “inhibition” or “inhibit” refer to a decrease or cessation of any event (such as protein ligand binding) or to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function, and/or amount as compared to a reference. It is not necessary that the inhibition or reduction be complete. For example, in certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20% or greater. In another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In yet another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater.

[0032] “Sample” or “subject sample” or “biological sample” generally refers to a sample which may be tested for a particular molecule. Samples may include but are not limited to cells, bone marrow, body fluids, including blood, serum, plasma, urine, saliva, stool, tears, pleural fluid and the like.

[0033] The terms "agent" and “test compound” are used interchangeably herein and denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Biological macromolecules include siRNA, shRNA, antisense oligonucleotides, peptides, peptide/DNA complexes, and any nucleic acid based molecule which exhibits the capacity to modulate the activity of the SNP containing nucleic acids described herein or their encoded proteins.

[0034] A “subject” can be mammalian. In any of the embodiments involving a subject, the subject can be human. In any of the embodiments involving a subject, the subject can be a cow, pig, monkey, sheep, dog, cat, fish, or poultry.

[0035] A “pediatric” subject herein is a human of less than 18 years of age, whereas an “adult” subject is 18 years or older.

[0036] The term “pharmaceutically acceptable composition” may refer to a composition comprising the anti-IL-18 antibody in formulations with a wide variety of pharmaceutically acceptable carriers.

[0037] The term “pharmaceutically acceptable carrier” refers to refers to an ingredient in a pharmaceutical formulation or composition, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, and/or preservative.

[0038] “Treatment” or “treat” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in which the disorder is to be prevented. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e. , not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0039] The term “effective amount” or “therapeutically effective amount” refers to an amount of a drug effective for treatment of a disease or disorder in a subject, such as to partially or fully relieve one or more symptoms. In some embodiments, an effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. [0040] The term “Eastern Cooperative Oncology Group Performance Status (ECOG PS) score as used herein refers to the score defined in Table 2 of Oken et al. (1982) Am J Clin Oncol. 5(6):649-55. An ECOG PS score of 0 means the subject is fully active, able to carry on all pre-disease performance without restriction. An ECOG PS score of 1 means the subject is restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. An ECOG PS score of 2 means the subject is ambulatory and capable of all selfcare but unable to carry out any work activities; the subject is up and about more than 50% of waking hours. An ECOG PS Score of 3 means the subject is capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. An ECOG PS Score of 4 means the subject is completely disabled, cannot carry on any selfcare, totally confined to bed or chair. An ECOG PS Score of 5 means the subject is dead.

[0041] The term “stringent complete response” or “sCR” as used herein refers to the score defined in the International Myeloma Working Group (IMWG) response criteria described in Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346. It is generally defined as negative immunofixation of the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow aspirates, plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (K/X ratio <4: 1 or >1 :2 for K and X patients, respectively, after counting >100 plasma cells).

[0042] The term “complete response” or “CR” as used herein refers to the score defined in the IMWG response criteria described in Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346. It is generally defined as negative immunofixation of the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow aspirates.

[0043] The term “very good partial response” or “VGPR” as used herein refers to the score defined in the IMWG response criteria described in Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346. It is generally defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or >90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hr.

[0044] The term “partial response” or “PR” as used herein refers to the score defined in the IMWG response criteria described in Kumar et al. (2016) Lancet Oncol. 17(8):e328- e346. It is generally defined as >50% reduction of serum M-protein plus reduction in 24-hr urinary M-protein by >90% or to <200 mg/24 hr. If the serum and urine M-protein are not measurable, a >50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M-protein and serum FLC assay are not measurable, >50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was >30%. In addition to the above criteria, if present at baseline, a >50% reduction in the size (sum of the products of the maximal perpendicular diameters of measured lesions (SPD)) of soft tissue plasmacytomas is also required.

[0045] The term “time to response” or “TTR” as used herein refers to the time from start of the treatment to the first observation of partial response or better. TTR is restricted to only subjects with confirmed responses.

[0046] The term “progression free survival” or “PFS” as used herein refers to the duration from start of the treatment to disease progression or death (regardless of cause of death), whichever comes first.

[0047] The term “duration of response” or “DOR” as used herein refers to the duration from the first observation of partial response to the time of disease progression, with deaths from causes other than progression censored. Duration of each complete response and partial response will be reported. DOR is restricted to only subjects with confirmed responses. For the purposes of the calculation of the DOR, as long as the response has been confirmed, the date at which the response status was first observed rather than the date of confirmation will be used as the start date.

[0048] “Relapsed/Refractory” or “R/R” or “RR” multiple myeloma, including “Active Relapsed/Refractory” multiple myeloma, as used herein refers to multiple myeloma that is relapsed, refractory, or relapsed and refractory. As used herein, relapsed/refractory multiple myeloma refers to a disease which becomes non-responsive or progressive on therapy or within 60 days of the last treatment in patients who had achieved a minimal response (MR) or better on prior therapy. Refractory disease means either (1) progressive disease on last prior therapy (progressive disease is defined in Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346); (2) best response of stable disease to last prior therapy (stable disease is defined in Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346); or (3) progressive disease within 3 months. Relapsed disease requires 1 or more of the following criteria: (1) direct indicators of increasing disease and/or end organ dysfunction (CRAB features) related to the underlying clonal plasma-cell proliferative disorder; it is not used in calculation of time-to-progression or PFS but is listed as something that can be reported optionally or for use in clinical practice; (2) development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression); (3) definite increase in the size of existing plasmacytomas or bone lesions; a definite increase is defined as a 50% (and >1 cm) increase as measured serially by the SPD of the measurable lesion; (4) hypercalcaemia (>11 mg/dL); (5) decrease in hemoglobin of >2 g/dL not related to therapy or other non- myeloma- related conditions; (6) rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma; and (7) hyperviscosity related to serum paraprotein. “Active” refers to multiple myeloma, as opposed to, for example, smoldering multiple myeloma. Multiple myeloma is defined, for example, in Rajkumar et al. (2014) Lancet Oncol. 15(12):e538-e548. Multiple myeloma is defined in Rajkumar et al. (2014) as clonal bone marrow plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: (1) evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: (i) hypercalcemia: serum calcium >0-25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2-75 mmol/L (>11 mg/dL); (ii) renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 pmol/L (>2 mg/dL); (iii) anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L; (iv) bone lesions: one or more osteolytic lesions on skeletal radiography, CT; or PET-CT; or (2) any one or more of the following biomarkers of malignancy: (i) clonal bone marrow plasma cell percentage >60%; (ii) involved: uninvolved serum free light chain ratio >100; (iii) >1 focal lesions on MRI studies.

[0049] “SPEP” or “serum protein electrophoresis” as used herein refers to a way to measure M-protein (also referred to as M protein) in a subject’s serum.

[0050] “M-protein” or “M protein” as used herein refers to myeloma protein, also referred to as monoclonal protein, which is a type of protein antibody (or fragment thereof, such as a light chain) produced by myeloma cells. The levels of this protein in the serum or urine are commonly used to diagnose multiple myeloma and to measure disease progression and/or response to therapy.

Anti-IL-18 Antibodies

[0051] In some embodiments, the anti-IL-18 antibody utilized for therapeutic purposes described herein comprises the CDR sequences and in some embodiments the heavy and light chain variable regions of Antibody 12_GL disclosed in WO 2012/085015, which is incorporated herein by reference in its entirety. Antibody 12 GL is referred to herein as Antibody A. Antibody A is a fully human IgGlK monoclonal antibody (mAb) binding and neutralizing IL- 18. [0052] Antibody A inhibits the formation of IL-18/Ra/RP active complex in-vitro and in-vivo. Antibody A demonstrates high affinity of 63 pM, which is 6 fold higher compared to IL-18’s native inhibitor (IL- 18 binding protein), and reduced Fc binding, to enable efficient anti-inflammatory role. As a fully human antibody, Antibody A is expected to demonstrate reduced anti-drug antibodies (ADA). Antibody A demonstrates IL-18 neutralization and bioactivity by reducing IL-18’s effects in various in vitro models with IC50 of sub nanomolar, and has proven efficient in COPD model (NHBE cells infected with Human Rhinovirus (HRV) by inhibiting IFN-y release from PBMCs exposed to infected NHBE media). Antibody A has undergone 13 weeks IV toxicity studies complete with no toxicity up to lOOmg/Kg/week.

[0053] In some embodiments, the anti-IL-18 antibody comprises the CDRs of Antibody A: (a) a HCDR1 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 122; (b) aHCDR2 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 123; (c) a HCDR3 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 124; (d) a LCDR1 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 126; (e) a LCDR2 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 127; and (1) a LCDR3 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 128.

[0054] In some embodiments, the anti-IL-18 antibody comprises the Antibody A VH domain (SEQ ID NO: 121) which may be paired with the Antibody A VL domain (SEQ ID NO: 125), so that an antibody antigen-binding site is formed comprising both the Antibody A VH and VL domains.

[0055] In some embodiments, an anti -IL-18 antibody is utilized for both the detection/diagnostic and therapeutic purposes described herein. In one embodiment, the anti- IL-18 antibody used for detection or diagnostic purposes is different from the antibody used for therapeutic purposes (even in the same subject).

[0056] In some embodiments, the anti-IL-18 antibody useful for therapeutic purposes may comprise the CDR sequences or heavy and light chain variable regions of the antibodies disclosed in WO 2012/085015, which is incorporated herein by reference in its entirety. The antibodies of WO 2012/085015 referred to herein include Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11 GL, and Antibody A. [0057] The anti-IL-18 antibody useful for therapeutic purposes may alternatively comprise the CDR sequences of other anti-IL-18 antibodies known in the art (see for example US6706487, WO 2001/058956, EP 1621616, US 2005/0147610; EP 0 974 600; and WO 0158956).

[0058] The anti-IL-18 antibody may alternatively comprise the CDR sequences or heavy and light chain variable regions of any of the antibodies disclosed in US 8,133,978 B2, which is incorporated herein by reference in its entirety. The antibodies of US 8,133,978 B2 referred to herein include the humanized anti-IL-18 antibodies referred to in claims 1 through 7 of US 8,133,978 B2. In some embodiments, the anti-IL-18 antibody is GSK1070806, which is a humanized IgGl/kappa antibody that binds to human IL-18 with a high affinity (Kd = 30.3 pM) and neutralizes its function. See, e.g., Reid, P. et al, Int J Clin Pharmacol Ther. 2014 Oct;52(10):867-79. doi: 10.5414/CP202087.

[0059] In some embodiments, the anti-IL-18 antibody of the invention inhibits the binding of IL- 18 to one or both of the IL- 18 receptor (IL-18R, which comprises IL-18Ra/IL- 18R[3) and IL-18BP and thereby reduces IL-18 activity. In some embodiments, the anti-IL-18 antibody may bind to an epitope on the IL-18 molecule which wholly or partially overlaps the IL-18BP binding site.

[0060] For example, the anti-IL-18 antibody may specifically bind to an epitope of IL-18 which comprises one or more of residues Tyrl, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56, Pro57, Arg58, Gly59, Met60, Argl04, Serl05 and Prol07 of human IL- 18 or the corresponding residues from IL- 18 of other species, for example a primate such as Rhesus macaque. The anti-IL-18 antibody may bind to an IL- 18 epitope which comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all 17 residues selected from the group consisting of Tyrl, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56, Pro57, Arg58, Gly59, Met60, Argl04, Serl05, and Prol07 of human IL-18.

[0061] In some embodiments, an anti-IL-18 antibody useful in the methods described herein may comprise one or more CDRs as described herein, e.g. a CDR3, and optionally also a CDR1 and CDR2 to form a set of CDRs. In some embodiments, the CDR or set of CDRs is a CDR or set of CDRs of any of Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11 GL, and Antibody A, or may be a variant thereof as described herein.

[0062] In some embodiments: HCDR1 may be about 7 amino acids long, comprising or consisting of Kabat residues 31 -35b; HCDR2 may be about 16 amino acids long, comprising or consisting of Kabat residues 50-65; HCDR3 may be about 15 amino acids long, comprising or consisting of Kabat residues 95-102; LCDR1 may be about 11 amino acids long, comprising or consisting of Kabat residues 24-34; LCDR2 may be about 7 amino acids long, comprising or consisting of Kabat residues 50-56; and/or LCDR3 may be about 9 amino acids long, comprising or consisting of Kabat residues 89-97. As is known in the art, in the variable region of the heavy chain, the CDR may include residues 31 to 35 plus an insertion of 2 residues, 35A and 35B.

[0063] In some embodiments, the anti-IL-18 antibody comprises aHCDRl, HCDR2 and/or HCDR3 and/or an LCDR1, LCDR2 and/or LCDR3 as provided in Table 6 (the CDRs belonging to an individual antibody). The anti-IL-18 antibody may comprise a VH as described in any one of the antibodies in the Table 6. Optionally, it may also comprise a VL of any one of these antibodies. The VL may be from the same or a different antibody as the VH. A VH domain comprising a set of HCDRs of any of the antibodies listed in the Table 6, and/or a VL domain comprising a set of LCDRs of any of the antibodies listed in the Table 6, are also provided herein.

[0064] In some embodiments, the anti-IL-18 antibody comprises Antibody A CDRs with amino acid residue substitutions: (a) aHCDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 122; (b) a HCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 123; (c) aHCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4 or 5 amino acid residue substitutions relative to SEQ ID NO: 124;(d) a LCDR1 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 126; (e) a LCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 127; and (1) a LCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acid residue substitutions relative to SEQ ID NO: 128.

[0065] In some embodiments, an anti-IL-18 antibody comprises a heavy chain and/or light chain of a parent antibody. In some embodiments, the anti-IL-18 antibody comprises any of the antibodies listed in the Table 6 with one or more substitutions within the CDRs. In some embodiments, the anti-IL-18 antibody comprises any of the antibodies listed in the Table 6 with one or more substitutions within the VH and/or VL. For example, an antibody molecule of the invention may comprise any one of Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11 GL, and Antibody A, with 17, 16 or 15 or fewer substitutions, e.g. 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 substitutions within the VH and/or VL. Substitutions may potentially be made at any residue, including within the set of CDRs.

[0066] Typically, a VH domain is paired with a VL domain to provide an antibody antigen-binding site, although as discussed above a VH or VL domain alone may be used to bind antigen. For example, the Antibody A VH domain (SEQ ID NO: 121) may be paired with the Antibody A VL domain (SEQ ID NO: 125), so that an antibody antigen-binding site is formed comprising both the Antibody A VH and VL domains. Analogous embodiments are provided for the VH and VL domains of the other antibodies disclosed herein.

[0067] In other embodiments, the Antibody A VH is paired with a VL domain other than that of Antibody A VL. Light-chain promiscuity is well established in the art. Again, analogous embodiments are provided by the invention for the other VH and VL domains disclosed herein. Thus, the VH of the parent Antibody 1 or of any of the optimised clones Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Antibody A may be paired with a VL domain from a different antibody e.g. the VH and VL domains may be from different antibodies selected from Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Antibody A.

[0068] In some embodiments, an anti-IL-18 antibody comprise a VH domain and a VL domain wherein; (i) the VH domain amino acid sequence is shown in SEQ ID NO: 121 and the VL domain amino acid sequence is shown in SEQ ID NO: 125, (ii) the VH domain amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid substitutions as compared to SEQ ID NO: 121 and the VL domain amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 amino acid substitutions as compared to SEQ ID NO: 125; or (iii) the VH domain amino acid sequence has at least 80%, at least 85%, at least 90% or at least 95% sequence identity with SEQ ID NO: 121 and the VL domain amino acid sequence has at least 80%, at least 85%, at least 90% or at least 95% sequence identity with SEQ ID NO: 125.

[0069] In some embodiments, the anti-IL-18 antibody comprises a VH domain having an amino acid sequence which is at least 90% identical to the full sequence of SEQ ID NO: 121. In some embodiments, the anti-IL-18 antibody comprises a VH domain having an amino acid sequence which is identical to the full sequence of SEQ ID NO: 121. In some embodiments, the anti -IL-18 antibody comprises a VL domain having an amino acid sequence which is at least 90% identical to the full sequence of SEQ ID NO: 125. In some embodiments, the anti -IL-18 antibody comprises a VL domain having an amino acid sequence which is identical to the full sequence of SEQ ID NO: 125. In some embodiments, the anti-IL-18 antibody comprises an antibody VH domain and an antibody VL domain, wherein the amino acid sequence of the antibody VH domain and the antibody VL domain are at least 90% identical to the full sequence of SEQ ID NOS: 121 and 125.

[0070] In some embodiments, the anti-IL-18 antibody comprises a heavy chain and light chain comprising the following complementarity determining regions (CDRs): (a) a HCDR1 comprising the amino acids of SEQ ID NO: 129; (b) a HCDR2 comprising the amino acids of SEQ ID NO: 130; (c) a HCDR3 comprising the amino acids of SEQ ID NO: 131; (d) a LCDR1 comprising the amino acids of SEQ ID NO: 132; (e) a LCDR2 comprising the amino acids of SEQ ID NO: 133; and (I) a LCDR3 comprising the amino acids of SEQ ID NO: 134.

[0071] In some embodiments, the anti-IL-18 antibody of the invention comprises: a heavy chain and light chain comprising the following complementarity determining regions (CDRs): (a) aHCDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 129; (b) a HCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 130; (c) aHCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4 or 5 amino acid residue substitutions relative to SEQ ID NO: 131; (d) a LCDR1 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 132; (e) a LCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 133; and (I) a LCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, or 4 amino acid residue substitutions relative to SEQ ID NO: 134.

[0072] In some embodiments, the IL-18 antibody comprises a heavy chain having an amino acid sequence identical to or comprising 1 to 12 amino acid residue substitutions relative to a heavy chain selected from the group consisting of: SEQ ID NO: 137, SEQ ID NO: 145, and SEQ ID NO: 149; and a light chain having an amino acid sequence identical to or comprising 1 to 12 amino acid residue substitutions relative to a light chain selected from the group consisting of: SEQ ID NO: 141 and SEQ ID NO: 157. In some embodiments, the anti-IL-18 antibody further comprises substituting the residue at position 71 of the light chain with the corresponding residue found in a donor antibody from which the CDRs are derived. In some embodiments, the anti-IL-18 antibody comprises a tyrosine at position 71 of the light chain. In some embodiments, the anti-IL-18 antibody comprises a phenylalanine at position 71 of the light chain.

[0073] In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 153. In one embodiment, the anti-IL-18 antibody the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 153. In one embodiment, the anti-IL-18 antibody the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 153.

[0074] In some embodiments, the anti-IL-18 antibody may lack antibody constant regions, for example a scFv.

[0075] In other embodiments, anti-IL-18 antibody may comprise an antibody constant region. The anti-IL-18 antibody may be a whole antibody such as an IgG, i.e. an IgGl, IgG2, or IgG4, or may be an antibody fragment or derivative as described below. Antibody molecules can also have other formats, e.g. IgGl with YTE (Dall’ Acqua et al. (2002) J. Immunology, 169: 5171-5180; Dall’Acqua et al. (2006) J Biol. Chem. 281(33):23514-24) and/or TM mutations (Oganesyan et al. (2008) Acta Cryst D64:700-4) in Fc region.

[0076] Another aspect of the invention provides an anti-IL-18 antibody comprising an antibody antigen binding site or antibody molecule as described herein which competes for binding to IL-18 with any antibody molecule which: (i) binds IL-18 and (ii) comprises an antibody molecule, VH and/or VL domain, CDR e.g. HCDR3, and/or set of CDRs listed in the Table 6.

[0077] For example, in some embodiments, the anti -IL-18 antibody may compete with an antibody molecule comprising: (i) a VH domain having the sequence of SEQ ID NO. 152 and a VL domain having the sequence of SEQ ID NO. 157; (ii) a VH domain having a sequence with 15 or fewer amino acid substitutions such as 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 as compared to SEQ ID NO. 152; and a VL domain having a sequence with 13 or fewer amino acid substitutions such as 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 as compared to or SEQ ID NO. 157, or; (iii) a VH domain and a VL domain having sequences with at least 90% sequence identity to SEQ ID NO. 152 and SEQ ID NO. 157, respectively.

[0078] Competition between anti-IL-18 antibodies may be assayed easily in vitro, for example using ELISA and/or by a biochemical competition assay such as one tagging a specific reporter molecule to one anti-IL-18 antibody which can be detected in the presence of one or more other untagged anti-IL-18 antibodies, to enable identification of anti-IL-18 antibodies which bind the same epitope or an overlapping epitope. Such methods are readily known to one of ordinary skill in the art and are described in more detail herein.

[0079] Variable domain amino acid sequence variants of any of the VH and VL domains whose sequences are specifically disclosed herein may be employed in accordance with the present invention.

[0080] As described above, aspects of the invention provide an anti-IL-18 antibody, comprising a VH domain that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with a VH domain of any of the antibodies listed herein, for which VH domain sequences are shown in the appended Table 6 below; and/or comprising a VL domain that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with a VL domain of any of the antibodies listed herein, for which VL domain sequences are shown in the appended Table 6 below.

[0081] Aspects of the invention provide an anti-IL-18 antibody comprising a VH domain having a set of VH CDRs that have at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with the set of VH CDRs of any of the antibodies listed herein, for which VH CDR sequences are shown in the appended Table 6; and/or comprising a VL domain having a set of VL CDRs that have at that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with the set of VL CDRs of any of the antibodies listed herein, for which the VL CDR sequences are shown in the appended Table 6. [0082] Algorithms that can be used to calculate % identity of two amino acid sequences are known in the art and include e.g. BLAST [Altschul et al. (1990) J. Mol. Biol. 215: 405-410], FASTA [Pearson and Lipman (1988) PNAS USA 85: 2444-2448], or the Smith-Waterman algorithm [Smith and Waterman (1981) J. Mol Biol. 147: 195-197] e.g. employing default parameters.

Pharmaceutical Formulations

[0083] The anti-IL-18 antibody may be administered in the form of a pharmaceutically acceptable composition. In various embodiments, compositions comprising anti-IL-18 antibodies are provided in formulations with a wide variety of pharmaceutically acceptable carriers (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Various pharmaceutically acceptable carriers, which include vehicles, adjuvants, and diluents, are available. Moreover, various pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are also available. Non-limiting exemplary carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.

[0084] In various embodiments, compositions comprising anti-IL-18 antibodies may be formulated for injection or infusion, by dissolving, suspending, or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other 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. In various embodiments, the compositions may be formulated for inhalation, for example, using pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen, and the like. The compositions may also be formulated, in various embodiments, into sustained release microcapsules, such as with biodegradable or non-biodegradable polymers. A non-limiting exemplary biodegradable formulation includes poly lactic acid-glycolic acid polymer. A non-limiting exemplary non- biodegradable formulation includes a polyglycerin fatty acid ester. Certain methods of making such formulations are described, for example, in EP 1 125 584 AL

[0085] Pharmaceutical packs and kits comprising one or more containers, each containing one or more doses of an anti-IL-18 antibody are also provided. In some embodiments, a unit dosage is provided wherein the unit dosage contains a predetermined amount of a composition comprising an anti-IL-18 antibody, with or without one or more additional agents. In some embodiments, such a unit dosage is supplied in single-use prefilled syringe for injection. In various embodiments, the composition contained in the unit dosage may comprise saline, sucrose, or the like; a buffer, such as phosphate, or the like; and/or be formulated within a stable and effective pH range. Alternatively, in some embodiments, the composition may be provided as a lyophilized powder that may be reconstituted upon addition of an appropriate liquid, for example, sterile water. In some embodiments, the composition comprises one or more substances that inhibit protein aggregation, including, but not limited to, sucrose and arginine. In some embodiments, a composition of the invention comprises heparin and/or a proteoglycan.

Treatment with Anti-IL-18 Antibodies

[0086] In some embodiments, a method of treating subjects having active relapsed/refractory (R/R) multiple myeloma is provided comprising administering an effective amount of an anti-IL-18 antibody to a human subject diagnosed with multiple myeloma.

[0087] In some embodiments, the subject has active multiple myeloma despite prior therapy with a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. Exemplary proteasome inhibitors include, but are not limited to, bortezomib, carfilzomib, and ixazomib. Exemplary immunomodulatory agents (IMiDs) (also referred to as immunomodulators) include, but are not limited to, thalidomide, lenalidomide, and pomalidomide. Exemplary anti-CD38 antibodies include, but are not limited to, daratumumab, daratumumab and hyaluronidase-fihj, and isatuximab.

[0088] In some embodiments, the subject has measurable myeloma based on any of the following: a) serum M-protein greater than 0.5 g/dL; urine M-protein greater than 200 mg/24 hours; serum free light chains greater than 10 mg/dL; and measurable plasmacytoma or extramedullary disease.

[0089] In some embodiments, the subject has an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1.

[0090] In some embodiments, the subject has undergone prior autologous hematopoietic stem cell transplantation more than 100 days prior to a screening visit.

[0091] In some embodiments, the subject is not administered an immunomodulatory drug at the same time as the anti-IL-18 antibody. In some embodiments, the immunomodulatory drug is selected from systemic glucocorticoids, anti-TNFa antibodies, anti-IL-17 antibodies, anti-IL-12/23 antibodies, PDE-4 inhibitors, JAK inhibitors, IL-6 inhibitors, rituximab, methotrexate, cyclosporine, and my cophenolate.

[0092] In some embodiments, the subject has elevated free or total serum or bone marrow IL-18. In some embodiments, the subject has elevated serum or bone marrow free or total IL- 18 levels compared to a subject without active R/R multiple myeloma or as compared to a negative control. In some embodiments, the anti -IL-18 antibody is administered in the form of a pharmaceutically acceptable composition.

[0093] In some embodiments, the level of serum or bone marrow IL-18 is measured prior to administration of the anti-IL-18 antibody. In some embodiments, the level of serum or bone marrow IL- 18 is measured after administration of the anti-IL-18 antibody as a marker for effectiveness of treatment. In some embodiments, the level of serum or bone marrow IL- 18 is free IL-18. In some embodiments, the level of free IL-18 is calculated. In some embodiments, the level of serum or bone marrow IL-18 is total IL-18.

[0094] In some embodiments, the anti-IL-18 antibody is administered for at least two 28-day treatment cycles, wherein the anti -IL-18 antibody is administered on day 1 of each 28-day treatment cycle. In some embodiments, the anti-IL-18 antibody is administered at a dose of 10, 30, 100, 300, or 1000 mg. In some embodiments, the anti-IL-18 antibody is administered at a dose of 10 to 30 mg/kg. In some embodiments, the anti-IL-18 antibody is administered at a dose of 0.03, 0.1, or 0.3 mg/kg. In some embodiments, the anti-IL-18 antibody is administered at a dose of 0.01 mg/kg to 36 mg/kg. In some embodiments, the anti-IL-18 antibody is administered at a dose of 4 mg/kg. In some embodiments, the anti-IL- 18 antibody is administered at a dose of 9 mg/kg. In some embodiments, the anti-IL-18 antibody is administered at a dose of 14 mg/kg.

[0095] In some embodiments, the anti-IL-18 antibody is administered intravenously. In some embodiments, the anti-IL-18 antibody is administered subcutaneously.

[0096] In some embodiments, the anti-IL-18 antibody is administered once per week. In some embodiments, the anti-IL-18 antibody is administered once every two weeks. In some embodiments, the anti-IL-18 antibody is administered once every three weeks. In some embodiments, the anti-IL-18 antibody is administered once every four weeks. In some embodiments, the anti-IL-18 antibody is administered once every five weeks. In some embodiments, the anti-IL-18 antibody is administered once every six weeks. In some embodiments, the anti-IL-18 antibody is administered on day 1 in 28-day treatment cycles. [0097] In some embodiments, the anti-IL-18 antibody is administered at a dose of 4 mg/kg on day 1 in 28-day treatment cycles. In some embodiments, the anti-IL-18 antibody is administered at a dose of 9 mg/kg on day 1 in 28-day treatment cycles. In some embodiments, the anti-IL-18 antibody is administered at a dose of 14 mg/kg on day 1 in 28- day treatment cycles.

[0098] In some embodiments, the subject is 18 years of age or older.

[0099] In some embodiments, administration of the anti-IL-18 antibody shortens time to response (TTR) compared to standard-of-care therapy. In some embodiments, administration of the anti-IL-18 antibody extends progression-free survival (PFS) compared to standard-of-care therapy. In some embodiments, administration of the anti-IL-18 antibody extends duration of response (DOR) compared to standard-of-care therapy.

[00100] In some embodiments, administration of the anti-IL-18 antibody results in the subject achieving a stringent complete response (sCR) according to International Myeloma Working Group (IMWG) response criteria after two or more 28-day treatment cycles. In some embodiments, administration of the anti-IL-18 antibody results in the subject achieving a complete response (CR) according to IMWG response criteria after two or more 28-day treatment cycles. In some embodiments, administration of the anti-IL-18 antibody results in the subject achieving a very good partial response (VGPR) according to IMWG response criteria after two or more 28-day treatment cycles. In some embodiments, administration of the anti-IL-18 antibody results in the subject achieving a partial response (PR) according to IMWG response criteria after two or more 28-day treatment cycles. In some embodiments, administration of the anti-IL-18 antibody results in the subject achieving an improved Eastern Cooperative Oncology Group Performance Status (ECOG PS) score.

[00101] In some embodiments, administration of the anti-IL-18 antibody results in the subject achieving a greater than or equal to 90% reduction in the subject’s serum M-protein as measured by SPEP. In some embodiments, the subject achieves such a score after one or more administrations of the anti-IL-18 antibody, e.g., 28-day treatment cycles. In some embodiments, administration of the anti-IL-18 antibody results in the subject achieving a greater than or equal to 50% reduction in the subject’s serum M-protein as measured by SPEP after one or more administrations of the anti-IL-18 antibody, e.g., 28-day treatment cycles. In some embodiments, administration of the anti-IL-18 antibody results in the subject achieving a greater than or equal to 25% reduction in the subject’s serum M-protein as measured by SPEP after one or more administrations of the anti-IL-18 antibody, e.g., 28-day treatment cycles, and wherein there is a less than or equal to 49% reduction in the subject’s serum M-protein as measured by SPEP after one or more administrations of the anti-IL-18 antibody, e.g., 28-day treatment cycles s. In some embodiments, administration of the anti- IL-18 antibody results in the subject achieving a reduction in the subject’s serum M-protein as measured by SPEP after one or more administrations of the anti-IL-18 antibody, e.g., 28- day treatment cycles. In some embodiments, the subject’s M-protein as measured by SPEP stabilizes after one or more administrations of the anti-IL-18 antibody, e.g., 28-day treatment cycles.

[00102] In some embodiments, the subject has undetectable levels of serum IL- 18 at about 28 days after administration of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum free IL- 18 at about 28 days after administration of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum IL-18 at about 112 days after administration of the first dose of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum free IL-18 at about 112 days after administration of the anti-IL-18 antibody. In some embodiments, the subject has reduced levels of bone marrow IL- 18 at about 28 days after administration of the anti-IL-18 antibody. In some embodiments, the subject has reduced levels of bone marrow IL- 18 at about 112 days after administration of the anti-IL-18 antibody.

Free IL-18 Detection Assays

[00103] Most currently available assays only measure total IL- 18, which includes IL- 18 bound to its receptors, including IL-18bp. Total IL- 18 may not provide as accurate of a picture of the levels of IL-18 causing disease, which may be free, unbound IL-18. Thus, it may be desirable to use an assay that measures free IL- 18 alone when the methods include detection of free IL- 18. Alternatively, free IL- 18 can be calculated based on total IL- 18 and total IL-18bp concentration data using formulas known in the art.

Kits And Articles of Manufacture

[00104] Any of the aforementioned methods can be implemented via kits for the detection and/or treatment of a condition associated with elevated IL-18, including multiple myeloma. The kit may contain an antibody, one or more non-naturally occurring detectable labels, marker, or reporter, a pharmaceutically acceptable carrier, a physiologically acceptable carrier, instructions for use, a container, a vessel for administration, an assay substrate, or any combination thereof. [00105] In some embodiments, the kit is for use in a method of detecting IL-18 in a biological sample. It may contain an anti-IL-18 antibody and reagents for carrying out the method.

[00106] In some embodiments, the kit is for use in a method of detecting IL-18 in a biological sample from a subject having or suspected of having multiple myeloma. It may contain an anti -IL-18 antibody and reagents for carrying out the method.

[00107] In some embodiments, the kit is for use in method of detecting elevated IL-18 in a biological sample from a subject, optionally wherein the subject is suspected of having multiple myeloma and also for treating the subject after diagnosis by administering an anti- IL-18 antibody in an effective amount. It may contain an anti-IL-18 antibody and reagents for carrying out the method.

[00108] In some embodiments, the kit for use in a method of detecting and/or treating comprises a solid phase to which the anti-IL-18 antibody reagent is attached. In some embodiments, the kit for use in a method of detecting and/or treating comprises a solid phase to which IL- 18 derived from the biological sample will be attached.

[00109] The solid phase to be used in the kits of the present invention includes, but is not limited, to microplates, magnetic particles, filter papers for immunochromatography, polymers such as polystyrene, glass beads, glass filters and other insoluble carriers. In one embodiment, a solid substrate containing many compartments or regions has at least one compartment coated with antibodies of the invention.

[00110] The kits of the invention may also include a further component to the diagnostic agent, the anti -IL- 18 antibody. The further component may include, but is not limited, reagents, enzymes for labeling, substrates therefor, radioisotopes, light-reflecting substances, fluorescent substances, colored substances, buffer solutions, and plates, and those mentioned herein above.

EXAMPLES

[00111] The following examples are provided to illustrate certain disclosed embodiments and are not to be construed as limiting the scope of this disclosure in any way. In the Examples discussed below, “Antibody A” refers to an anti-IL-18 antibody, wherein the anti-IL-18 antibody comprises the following six CDRs: a heavy chain CDR having an amino acid sequence of SEQ ID NO: 122; a heavy chain CDR having an amino acid sequence of SEQ ID NO: 123; a heavy chain CDR having an amino acid sequence of SEQ ID NO: 124; a light chain CDR having an amino acid sequence of SEQ ID NO: 126; a light chain CDR having an amino acid sequence of SEQ ID NO: 127; and a light chain CDR having an amino acid sequence of SEQ ID NO: 128. In some embodiments Antibody A has a variable heavy chain (VH) having an amino acid sequence of SEQ ID NO: 121 and a variable light chain (VL) having an amino acid sequence of SEQ ID NO: 125.

Example 1 - A Multicenter, Open-Label, Dose-Escalation Phase lb Study Of Antibody A In Subjects With Relapsed/Refractory Multiple Myeloma

Example 1.1 - Study Objectives

[00112] The primary objective of the study is to determine the recommended Phase 2 dose (RP2D) of Antibody A in subjects with relapsed/refractory (R/R) multiple myeloma. The RP2D may be based on safety findings (e.g., on the finding of dose-limiting toxicity [DLT]), PK findings, and/or pharmacodynamic (PD) findings.

[00113] The secondary objectives of the study are: to assess the safety profile of Antibody A in R/R multiple myeloma; to assess the PK profile of Antibody A; to assess the anti-myeloma activity of Antibody A based on International Myeloma Working Group (IMWG) criteria for response; to determine the incidence of AD As to Antibody A; and to determine the time to response (TTR), progression-free survival (PFS), and duration of response (DOR).

[00114] The exploratory objectives are to assess the effect of Antibody A on serum IL- 18 levels and other inflammatory biomarkers (InflammationMAP assay) and IL-18 levels in bone marrow (solubilized B cell maturation antigen (sBCMA) levels will be evaluated at the same time points), and also to assess the effect of Antibody A on levels of bone marrow and peripheral blood myeloid-derived suppressor cells.

Example 1.2 - Study Design

Overall Study Design and Plan

[00115] This is a multicenter, open-label, dose-escalation, sequential groups Phase lb clinical study in subjects with R/R multiple myeloma. The trial utilizes a “3+3” design. Initially, three subjects were enrolled at each dose, starting with the initial dose of 4 mg/kg. If there were no DLTs, escalation to the next cohort would take place. If there is 1 DLT, then the cohort will be expanded to 6. If there are no further DLTs, then escalation to the next dose will take place. If there are 2 DLTs in the initial 3 subjects, or 2 in the expanded cohort of 6 subjects, then the maximally tolerated dose will have been exceeded and dose escalation will stop. The dose prior to the dose where DLT was observed will then be the RP2D. [00116] Subjects must be> 18 years of age, and have active R/R multiple myeloma. Subjects must have measurable myeloma; an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; adequate hematopoietic, renal and hepatic function; and in those subjects who have undergone prior autologous hematopoietic stem cell transplantation, more than 100 days prior to the Screening Visit must have elapsed.

[00117] Subjects will not be eligible if they have currently active infection requiring use of systemic antimicrobial therapy, received more than 6 prior treatment regimens (for dose expansion phase), have received corticosteroids (>10 mg/daily prednisone or equivalent) or chemotherapy within 2 weeks of study drugs (4 weeks for nitrosourea, melphalan or monoclonal antibodies), have had another malignancy within 1 year of study entry with high probability of recurrence, have had any clinically significant medical condition that would interfere with the conduct of study evaluations, are pregnant or nursing, have been previously treated with an anti-IL-18 antibody, or have clinically significant abnormal laboratory findings.

[00118] Antibody A will be and was administered by IV infusion over 1 hour on Day 1 of each 28-day treatment cycle at doses of 4, 9, or 14 mg/kg, until disease progression or toxicity. Intermediate doses may also be explored based on the recommendation of the safety review committee (SRC).

[00119] All subjects will be and were monitored for adverse events (AEs) and will and did undergo physical exams, ECOG status examination, electrocardiograms (ECGs) and routine safety laboratory testing to describe the safety profile of Antibody A. Efficacy will be determined by the IMWG criteria for response. The PK of Antibody A will be based on serum levels obtained at various time points after administration, and the PD will be based on serum IL- 18 levels and other inflammatory markers (InflammationMAP assay) also obtained at various time points after administration of Antibody A. sBCMA levels will be measured at the same time points. Levels of bone marrow and peripheral blood myeloid-derived suppressor cells will be analyzed after administration of Antibody A at selected sites.

[00120] Subjects who discontinue from the study due to reasons other than disease progression will need to be followed every 30 days until documentation of disease progression or initiation of a new therapy for their disease. Once disease progression is documented or new therapy is initiated, the subject will move into the survival follow-up stage of the study.

[00121] All subjects will have to visit the site for a follow-up 30 days after the last dose of study drug. There will be a telephonic follow-up 60 days after the last dose. All subjects will be followed every 3 months for survival for a period of 1 year after the last dose of study drug. Subsequent therapy information and survival information will be collected via a telephone contact.

[00122] Definition of Recommended Phase 2 Dose

[00123] The RP2D may be the dose prior to the dose where DLT was observed. The RP2D may be based on safety findings (e.g., on the finding of DLT), PK findings, and/or PD findings.

[00124] Definition of Dose-Limiting Toxicity

[00125] The following AEs will be considered a DLT if occurring in Cycle 1 (within 28 days of first dose) and are deemed to be related to Antibody A treatment: any non- hematologic AE Grade >3; febrile neutropenia or neutropenia Grade 4 lasting >7 days; thrombocytopenia Grade 4 lasting >7 days or Grade 3 or 4 thrombocytopenia with clinically significant bleeding; any AE leading to a delay in the start of Cycle 2.

[00126] Discussion of Study Design

[00127] This dose escalation study will determine the RP2D of Antibody A administered via an IV infusion in subjects with R/R multiple myeloma. The RP2D will be determined based on safety (DLT), PK, and/or PD findings of this study. The study will use “3+3” dose escalation design, which is a commonly used design for dose escalation studies, and which minimizes exposure to sub-therapeutic doses, as well as minimizing exposure to potentially toxic, higher doses. Dose-limiting toxicity will include any Grade >3 AEs for which there is no explanation other than the effect of Antibody A occurring within the first 28 days of therapy. Following the determination of the RP2D, an expansion cohort may be opened.

Inclusion Criteria

[00128] Subjects must fulfill the following requirements to be eligible for the study:

1. Subj ect has active R/R multiple myeloma.

2. Subject has measurable myeloma based on any of the following: a. Serum M-protein > 0.5 g/dL b. Urine M-protein > 200 mg/24 hours c. Serum free light chain (FLC) > 10 mg/dL d. Measurable plasmacytoma or extramedullary disease

3. Subject has active myeloma despite prior therapy with a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody.

4. Subject has an ECOG PS score of 0 or 1. 5. Subject is > 18 years of age.

6. Subject has adequate hematopoietic, renal and hepatic function, defined as: a. Absolute neutrophil count > 1,000/pL; platelet count > 75,000/pL in patients with < 50% marrow involvement b. Absolute neutrophil count > 750/pL; platelet count > 50,000/pL in patients with > 50% marrow involvement c. Serum creatinine < 2.5 mg/dL or calculated creatinine clearance of > 30 mL/min according to the Cockcroft-Gault equation d. Aspartate transaminase/alanine transaminase < 3* the upper limit of normal (ULN) and total bilirubin < 2* the ULN

7. If applicable, the subject has undergone prior autologous hematopoietic stem cell transplantation more than 100 days prior to the Screening Visit.

8. Female patients of childbearing potential who are heterosexually active and male patients with female sexual partners of childbearing potential must agree to use an effective method of contraception (e.g., oral contraceptives, double-barrier methods such as a condom and a diaphragm, intrauterine device) or abstain from sexual activity during the study and for 220 days (5 half-lives) following the last dose of study medication, or to abstain from sexual intercourse for the duration of study participation. A woman not of childbearing potential is one who has undergone bilateral oophorectomies or who is postmenopausal, defined as the absence of menstrual periods for 12 consecutive months.

9. Subject has provided written informed consent for this study.

Exclusion Criteria

[00129] The presence of any of the following criteria excludes a subject from the study:

1. Subj ect has currently active infection requiring use of systemic antimicrobial therapy.

2. Dose expansion phase: Subject has received more than 6 prior treatment regimens.

3. Subject has received corticosteroids (>10 mg/daily prednisone or equivalent) or chemotherapy within 2 weeks of study drugs (4 weeks for nitrosourea, melphalan or monoclonal antibodies.

4. Subject has hyperviscosity syndrome.

5. Subject has central nervous system involvement by myeloma, including leptomeningeal involvement.

6. Subject is judged to be at risk for impending fracture.

7. Subject has known amyloidosis or POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) syndrome.

8. Subject had another malignancy within 1 year of study entry with high probability of recurrence.

9. Subject is pregnant or lactating.

10. Subject has a history of, or tests positive for, hepatitis B, untreated hepatitis C or human immunodeficiency virus (HIV). Subject with hepatitis C who has received a full course of anti-viral therapy or who is currently receiving anti-viral therapy with undetectable levels of hepatitis C RNA, is eligible for the trial.

11. Subject has undergone major surgery or trauma within 4 weeks of study entry.

12. Subject has been previously treated with an anti-IL-18 antibody.

13. Subject is currently taking immunomodulatory drugs, including pharmacologic doses of systemic glucocorticoids (> 10 mg prednisone daily or equivalent), anti-TNFa antibodies, anti-IL-17 antibodies, anti-IL- 12/23 antibodies, phosphodiesterase-4 (PDE-4) inhibitors, janus kinase (JAK) inhibitors, IL-6 inhibitors, rituximab, methotrexate, cyclosporine, mycophenolate.

14. Subject with known active autoimmune disorders including, but not limited to, rheumatoid arthritis, lupus, systemic sclerosis, Sjogren’s syndrome, psoriatic arthritis, ulcerative colitis, Crohn’s disease, vasculitis, multiple sclerosis. Subjects with autoimmune endocrinopathies on stable doses of replacement hormone therapy are eligible for the trial.

15. Subject has had a prior allogeneic transplant.

16. Subject has New York Heart Association (NYHA) Class III or IV Congestive Heart Failure (CHF), myocardial infarction or acute coronary syndrome within 6 months prior to the Screening Visit, ongoing angina pectoris, severe peripheral vascular disease, or any other concomitant medical disorder that might interfere with the subject’s participation in the trial or interpretation of the study data.

17. Subject has psychiatric, substance abuse, or social conditions that would interfere with the subject’s participation or cooperation with the requirements of the trial.

18. Subject has known hypersensitivity to any of the components of Antibody A.

Screen Failures

[00130] Subjects who fail inclusion and/or exclusion criteria may be rescreened once for the study with the prior approval of the Medical Monitor. In the event of a rescreening, the first screening visit will be entered into the electronic case report form (eCRF) as the Screening Visit and the repeat assessments entered into the eCRF as an unscheduled visit.

Premature Subject Withdrawal

[00131] All subjects will be advised that they are free to withdraw from participation in this study at any time, for any reason, and without prejudice. Every reasonable attempt should be made by the investigator to keep subjects in the study; however, subjects must be withdrawn from the study if they withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend scheduled visits by telephone or other means to exclude the possibility of an AE being the cause of withdrawal. Should this be the cause, the AE must be documented, reported, and followed. [00132] The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or other reasons.

[00133] The investigator also has the right to withdraw subjects from the study at any time for any reason. If a subject is withdrawn before completing the study, the subject should be followed-up as instructed in the Schedule of Assessment (Table 1). The reason for withdrawal must be determined by the investigator and recorded in the subject’s medical record and on the case report form (CRF). If a subject is withdrawn for more than 1 reason, each reason should be documented in the source document and the most clinically relevant reason should be entered on the CRF.

[00134] Reasons for discontinuation include but are not limited to:

• Progression of myeloma

• Adverse event

• The need for a prohibited concomitant medication

• Major protocol deviation

• Withdrawal by the investigator in the best interests of the subject

• Withdrawal by subject

• Lost to follow-up

• Other. If Other is selected, the investigator must specify the reason on the CRF.

Subject Replacement Criteria

[00135] Subjects who withdraw from the study during the first treatment cycle for reasons other than a DLT may be replaced.

Table 1: Schedule of Assessments

Table 1: Schedule of Assessments

Table 1: Schedule of Assessments

Example 1.3 - Treatments

Identification of Investigational Product(s), Dose and Mode of Administration

[00136] Antibody A was provided as a lyophilized powder in a 3 mL single-use glass vial. Each vial contains 50 mg of Antibody A and was reconstituted with 1.2 mL of water for injection. An appropriate amount of reconstituted Antibody A was further diluted in normal saline and infused over 1 hour. Antibody A was administered by intravenous infusion at doses of 4 mg/kg (maximum dose 300 mg), 9 mg/kg (no change from prior), or 14 mg/kg (maximum dose 1000 mg; no change from prior) on Day 1 of each 28-day treatment cycle until disease progression or toxicity. Intermediate doses may also be explored based on the recommendation of the SRC.

Treatments Administered

[00137] Eligible subjects will and did receive Antibody A on Day 1 of each 28-day treatment cycle at doses of 4 mg/kg (maximum dose 300 mg), 9 mg/kg (no change from prior), or 14 mg/kg (maximum dose 1000 mg; no change from prior) via intravenous infusion over 1 hour, until disease progression or toxicity.

Blinding and Unblinding Treatment Assignment

[00138] This is an open-label study.

Selection of Doses in the Study

[00139] The doses of 4, 9, and 14 mg/kg, administered on Day 1 of every 28-day treatment cycle, will be used in this study.

Dose Adjustment Criteria

[00140] No dose adjustment for an individual subject is planned in this study.

Prior Therapies

[00141] Prior therapies includes all treatments received within 28 days of the date of first dose of investigational product.

Concomitant Therapies

[00142] Concomitant therapies refer to all therapies taken between the dates of the first dose of investigational product and the end of the follow-up period, inclusive. Concomitant therapy information must be recorded on the appropriate CRF page. Permitted Therapies

[00143] Patients are treated for all intercurrent medical conditions at the discretion of the investigator in accordance with community standards of medical care. Subjects receive treatments for palliation of symptoms associated with myeloma such as analgesics (both opioid and non-opioid), antibiotics, transfusions, etc. Patients may receive denosumab or other bone agents as long as they have been on such agents for at least 3 months prior to Day 1 of the study (discuss with Medical Monitor as necessary). The use of inhaled bronchodilators is allowed, if needed. Antibiotics and OTC medications considered necessary for the subject’s welfare, may be administered at the discretion of the investigator.

[00144] Subject’s vaccination status should be reviewed in accordance with current immunization guidelines prior to study start and it is recommended that vaccination be avoided within 4 weeks of initiating treatment with Antibody A.

Prohibited Therapies

[00145] Any therapy designed to treat the subject’s underlying myeloma is prohibited during the trial. Subjects who need to undergo palliative radiation may be permitted to do so following a discussion with the sponsor’s medical monitor.

[00146] During the study, new initiation of investigational compounds is prohibited.

[00147] The use of immunomodulatory drugs is prohibited. Immunomodulatory drugs include pharmacologic doses of systemic glucocorticoids (> 10 mg prednisone daily or equivalent), anti-TNFa antibodies, anti-IL-17 antibodies, anti-IL- 12/23 antibodies, PDE-4 inhibitors, JAK inhibitors, IL-6 inhibitors, rituximab, methotrexate, cyclosporine, mycophenolate. Intranasal, intra-ocular, inhalational and intra-articular glucocorticoids are permitted.

[00148] At the discretion of the sponsor, subjects receiving excluded therapies during the study may be ineligible for continuation in the study.

Treatment after End of Study

[00149] Following discontinuation from the study, subjects may be treated at the discretion of the investigator. Example 1.4 - Study Procedures

Study Duration

[00150] The sequence and maximum duration of the study periods will be as follows. The screening period will be approximately 28 days. For the treatment period, subjects will receive study drug on Day 1 of each 28-day treatment cycle, until toxicity or disease progression. For follow-up, subjects will be contacted for safety assessment at 60 days after the last dose of investigational product. Survival follow-up will be every 3 months for a period of 1 year after the last dose of investigational product.

Safety Assessments

[00151] Safety and tolerability assessments will include the frequency and severity of AEs as well as the evaluation of changes in clinical laboratory values, vital signs, ECG recordings, ECOG PS score, and physical examination findings.

Clinical Laboratory Tests to be Performed

[00152] Samples for the following clinical laboratory tests will be collected at the time points specified in the Schedule of Assessments (Table 1).

[00153] Hematology tests include hemoglobin, hematocrit, platelet count (or estimate), and white blood cell count including differential.

[00154] Serum chemistry tests include albumin, total bilirubin, total protein, calcium, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, magnesium, glucose, sodium, potassium, chloride, bicarbonate, phosphorous, and uric acid.

[00155] A coagulation panel will include partial thromboplastin time and international normalized ratio.

[00156] A serum pregnancy test will be administered for females of childbearing potential.

[00157] Urinalysis tests include pH, specific gravity, dipstick determinations of protein, blood, glucose and ketones; and microscopic if blood or protein 2+ or higher.

[00158] Laboratory specimens will be analyzed at local laboratory facilities per their collection and processing requirements.

Sampled Blood Volume

[00159] The sampled blood volume for the first two cycles in this study is shown in Table

2. Table 2: Sampled Blood Volume per Subject

Note: These sample blood volumes are for the screening and first two cycles only.

Abbreviations: FLC = free light chain; MDSC = myeloid-derived suppressor cells; SPEP = serum protein electrophoresis. Evaluation of Laboratory Values

[00160] The normal ranges of values for the laboratory assessments in this study will be provided by the local laboratory facility. They will be regarded as the reference ranges on which decisions will be made for the specific site.

[00161] If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The investigator must evaluate the out-of-range values and record his/her assessment of the clinical relevance in the subject’s source documentation. Abnormal laboratory values may be considered AEs if they are clinically significant; if they require an intervention; or if they change the administration of study drug.

[00162] All laboratory values which, in the investigator’s opinion, show clinically relevant or pathological changes during or after termination of the treatment are to be discussed with the medical monitor, as necessary, and reported as AEs and followed.

Clinical Examination: Vital Signs

[00163] Blood pressure, pulse rate, respiratory rate, temperature, and body weight will be measured at times specified in the Schedule of Assessments (Table 1). Additional blood pressure and pulse rate measurements may be performed, as determined by the investigator, to ensure appropriate monitoring of subject safety and accurate recording of vital sign measurements. Any changes from baseline which are deemed clinically significant by the investigator are to be recorded as an AE.

Clinical Examination: Electrocardiogram

[00164] A standard 12-lead ECG will be performed after the subject has been supine for approximately 5 minutes. All ECG recordings will be identified with the subject number, date, and time of the recording and a copy will be included with the subject’s source documentation.

[00165] Twelve-lead ECGs will be performed at screening, cycle 1 day 1, and then as required. An ECG that has been performed within 6 months of screening will be accepted as long as there has been no incidence of new cardiac symptoms or event (Table 1). All ECG values which, in the investigator’s opinion, show clinically relevant or pathological changes during or after termination of the treatment are to be discussed with the medical monitor and reported as AEs and followed.

Clinical Examination: Physical Examination

[00166] A complete physical examination will be performed at the Screening Visit before potential exposure to the investigational product and at the end of study (Table 1). Additionally, on days of treatment administration, targeted physical examination will be done focusing on areas of myeloma involvement or on AEs. Any clinically significant physical examination findings are to be and reported as AEs and followed.

[00167] Clinical Examination: ECOG Performance Status

[00168] ECOG PS assessments (Oken et al. (1982) Am J Clin Oncol. 5(6):649-55) will be performed during the study to assess how the disease affects the daily living abilities of the subjects.

Clinical Examination: Adverse Events

[00169] The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE described previously. At each visit, the subject will be allowed time to spontaneously report any issues since the last visit or evaluation.

[00170] Any clinically relevant observations made during the visit will also be considered AEs.

[00171] Pharmacokinetics

[00172] Blood draws for PK analysis will be performed in accordance with Table 1. [00173] Serum samples will be analyzed via validated methods for serum Antibody A concentrations.

[00174] Pharmacokinetic endpoints may include, but are not limited to, estimations of Cmax, ti/2, CL, volume of distribution (Vd), and area under the concentration-time curve from time 0 to time t (AUCo^t).

Efficacy

[00175] Efficacy will be assessed by the procedures described in the following subsections and graded according to the IMWG response criteria summarized in Table 3 (Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346). All multiple myeloma disease assessments outlined below are required to be performed at the study visits specified in Table 1 and the investigator should make all attempts to collect all multiple myeloma disease assessments at each time point. Response assessments will be performed during each cycle with a window allowing disease status assessment prior to administration of the next scheduled dose.

[00176] Two consecutive assessments are needed to confirm response (Table 3). For subjects who achieve complete response (CR) or stringent complete response (sCR), confirmatory samples for serum protein electrophoresis (SPEP) with serum protein immunofixation, quantitative Ig, and serum FLC must be collected in duplicate at the time of response and the duplicate samples must be provided to the local laboratory facility.

Table 3: IMWG Response Criteria

Source: Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346. Abbreviations: ASCT = autologous stem-cell transplantation; CR = complete response; CRAB features = calcium elevation, renal failure, anemia, lytic bone lesions; CT = computed tomography; DOR = duration of response; FDG = fluorodeoxy glucose; FLC = free light chain; hr = hour; Ig = immunoglobulin; IMWG = International Myeloma Working Group; MM = multiple myeloma; MR = minimal response; MRD = minimal residual disease; MRI = magnetic resonance imaging; PD = progressive disease; PET = positron emission tomography ; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; SD = stable disease; SPD = sum of the products of the maximal perpendicular diameters of measured lesions; VGPR= very good partial response. a All response categories require 2 consecutive assessments made any time before starting any new therapy. b All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained with the validated Freelite test (Binding Site, Birmingham, United Kingdom). c Presence/absence of clonal cells on immunohistochemistry is based upon the K/X/L ratio. An abnormal K/X ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abo of an abnormal clone is K/X of >4: 1 or <1:2. d Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD. e Positive immunofixation alone in a patient previously classified as achieving a CR will not be considered progression. For purposes of calculating time-to-progression and PFS, patients who have achieved a CR and are MRD-negative should be evaluated using criteria listed for PD. f In the case where a value is felt to be a spurious result per Investigator discretion (eg, a possible laboratory error), that value will not be considered when determining the lowest value.

SPEP

[00177] SPEP with monoclonal protein band (M-spike) quantification and serum protein immunofixation will be performed to assess response.

UPEP

[00178] Urine protein electrophoresis (UPEP; 24-hour urine) with M-spike quantification and urine protein immunofixation will be performed to assess response in subjects who do not have an M-spike on SPEP.

[00179] Quantitative Immunoglobulin Levels

[00180] If SPEP is felt to be unreliable for routine M-protein measurement (eg, patients with immunoglobulin A or immunoglobulin D myeloma), then quantitative Ig levels will be obtained.

[00181] Serum FLC will be performed to assess response in patients for whom serum FLC represents the patient’s myeloma protein.

[00182] Skeletal Survey

[00183] A baseline skeletal survey will be performed using X-rays and/or other clinically appropriate imaging modalities (eg, magnetic resonance imaging ([MRI], whole body computed tomography [CT], or positron emission tomography [PET]/CT) as determined by the investigator. [00184] The skeletal survey should include a lateral radiograph of the skull, anterioposterior and lateral views of the spine, and anterioposterior views of the pelvis, ribs, femora, and humeri.

[00185] If lytic bone lesions or plasmacytomas are observed at baseline, their number and size should be recorded in the eCRF. Follow-up assessments of bone lesions and/or plasmacytomas need only be conducted to document response or progression.

[00186] For subjects without soft tissue plasmacytomas (i.e., bone lesions only), skeletal survey by X-rays or low-dose CT should be performed. Contrast is not required.

[00187] For subjects with soft tissue plasmacytomas, skeletal survey by X-rays or low- dose CT should be performed (contrast not required) and in addition MRI or CT or PET/CT, usually requiring contrast enhancement, should be performed.

[00188] Bone Marrow Aspirate and Biopsy

[00189] A bone marrow aspirate will be collected at screening to confirm the diagnosis of multiple myeloma. After initiating study treatment, bone marrow aspirate will be collected in accordance with Table 1.

[00190] A bone marrow aspirate is required at the time of response for patients who achieve CR or sCR, unless after consultation with the Medical Monitor the collection and/or processing of the sample is not considered to be feasible.

[00191] A portion of the bone marrow aspirate and slides from the bone marrow biopsy collected at the time of response will be provided to the local laboratory.

[00192] Bone marrow aspiration may also be performed, as clinically indicated, to assess progression.

Immunogenicity

[00193] Blood draws for immunogenicity analysis will be performed in accordance with Table 1. Details of immunogenicity sample collection and processing can be found in the site and/or study laboratory manual. Serum samples will be analyzed via validated methods for ADA determination. The incidence of ADA against Antibody A will be determined.

[00194] Pharmacodynamics

[00195] The PD will be determined by measuring serum IL- 18 levels and other inflammatory markers (InflammationMAP assay) obtained at various time points after administration of Antibody A (Table 1). sBCMA levels will be measured at the same time points.

[00196] Levels of bone marrow and peripheral blood myeloid derived suppressor cells will be analyzed after administration of Antibody A at the times mentioned in the Schedule of Assessments (Table 1).

Example 1.5 - Adverse Events

Adverse Event Collection

[00197] An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with the product. An AE can therefore be any unfavorable and unintended sign (including a new, clinically important abnormal laboratory finding), symptom, or disease, temporally associated with the product, whether or not related to the product. An AE will be considered treatment-emergent if it occurs after the first dose of investigational product and within 60 days of a subject’s last dose of investigational product.

[00198] All AEs are collected from the time of first dose administration (Cycle 1, Day 1) through the 60-day follow-up period (Table 1). This includes events occurring during the screening phase of the study, regardless of whether investigational product is administered. Where possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, then each symptom should be listed individually. All AEs should be captured on the appropriate AE pages in the eCRF and in source documents.

[00199] All AEs must be followed to closure (the subject’s health has returned to his/her baseline status or all variable have returned to normal), regardless of whether the subject is still participating in the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator does not expect any further improvement or worsening of the event), or the event is otherwise explained. When appropriate, medical tests and examinations are performed so that resolution of an event(s) can be documented.

Severity of Adverse Events

[00200] The severity of AEs will be based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 and must be recorded during the course of the event including the start and stop dates for each change in severity. An event that changes in severity should be captured as a new event. Worsening of pre-treatment events, after initiation of investigational product must be recorded as new AEs. For example, if the subject experiences mild, intermittent headaches prior to dosing with investigational product; however the headache intensity increases to moderate after the first dose of investigational product, a new AE of moderate intermittent headaches is to be recorded in the source documents and eCRF. For events not listed in the CTCAE, severity will be determined using the following definitions. Mild is defined as usually transient and may require only minimal treatment or therapeutic intervention; the event does not generally interfere with usual activities of daily living. Moderate is defined as usually alleviated with additional specific therapeutic intervention; the event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the subject. Severe is defined as interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Life-threatening is defined as the subject was in immediate danger of dying from the event as it occurred. Fatal is defined as the event resulted in the death of the subject.

[00201] It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity whereas an SAE is an AE that meets serious criteria.

Relationship Categorization

[00202] A physician investigator must make the assessment of relationship to investigational product for each AE. The investigator should decide whether, in his or her medical judgment, there is a reasonable possibility that the event may have been caused by the investigational product. If there is no valid reason for suggesting a relationship, then the AE should be classified as “not related”. Otherwise, the AE should be categorized per the guidelines below. The causality assessment must be documented in the source document and the eCRF (Table 4).

Table 4: Assessment of Relationship to Investigational Product

AE = adverse event.

Outcome at the Time of Last Observation

[00203] The outcome at the time of last observation will be classified as: recovered/resolved; recovered/resolved with sequelae; recovering/resolving; not recovered/not resolved; fatal; or unknown.

Reporting of Serious Adverse Events

[00204] Initial and follow-up SAE reports must be completed by the investigator or designee and sent to the contract research organization (CRO) within 24 hours of the first awareness of a SAE. The investigator or designee must complete, sign and date the appropriate SAE form and verify the accuracy of the information against corresponding source documents. This information is to be sent to the CRO Pharmacovigilance Department.

Serious Adverse Event Definition

[00205] An SAE is any untoward medical occurrence, whether considered to be related to investigational product or not, that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly; or is an important medical event. [00206] Note that the term “life-threatening” in the definition of “serious” refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

[00207] Note that inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. An elective hospital admission to treat a condition present before exposure to the test drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, organization, or accommodation problems and without medical background does not need to be considered an SAE.

[00208] Note that a congenital anomaly in an infant born to a mother who was exposed to the investigational product during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has received an investigational product is not considered an SAE unless it is suspected that the investigational product interacted with a contraceptive method and led to the pregnancy.

[00209] Note that medical and scientific judgment should be exercised in deciding whether it is appropriate to consider other situations serious, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

Serious Adverse Event Collection Time Frame

[00210] All SAEs, regardless of the relationship to study, are collected from the time the subject signs the informed consent until the subject’s last visit (office or telephone contact). The investigator or designee must report all SAEs promptly to the CRO within 24 hours of first becoming aware of the event.

[00211] Any SAE(s), regardless of relationship to study, discovered by the investigator at any interval after study has completed must be reported to CRO within 24 hours of the first awareness of the event. Serious Adverse Event Onset and Resolution Dates

[00212] The onset date of the SAE is defined as the date the event meets serious criteria. The resolution date is the date the event no longer meets serious criteria, the date symptoms resolve or the event is considered chronic. In the case of hospitalization, the hospital admission and discharge dates are considered respectively, the onset and resolution date of the SAE.

[00213] Any signs or symptoms experienced by the subject after signing the informed consent form, or leading up to the onset date of the SAE or following the resolution date of the SAE must be recorded as an AE.

Fatal Outcome

[00214] Fatal should only be designated as an outcome when the AE results in death. If more than 1 AE is possibly related to the subject’s death, the outcome of death should be indicated for each such AE.

[00215] Any AE that results in the subject’s death must have fatal checked as an outcome with the date of death recorded as the resolution date. AEs resulting in death must be reported within 24 hours as a SAE, if not already reported as such.

[00216] For other AEs, ongoing at the time of death that did not contribute to the subject’s death, the outcome should be considered not resolved, without a resolution date recorded.

Adverse Events of Special Interest

[00217] The following events will be considered as AEs of special interest during this study: immunosuppression (decreased white counts, thrombocytopenia, anemia) and increased tumor frequency.

Pregnancy

[00218] All females of childbearing potential who participate in the study should be counseled on the need to practice adequate birth control and on the importance of avoiding pregnancy during study participation. Females should be instructed to contact the investigator or study staff immediately if pregnancy occurs or is suspected.

[00219] Pregnancy testing will be conducted on every female at screening and end of study. A female who is found to be pregnant at screening will be excluded from the study and considered to be a screening failure. A female who is found to be pregnant after the dosing is required to be discontinued from the study and the end of study visit assessments performed as soon as possible after learning of the pregnancy. [00220] The investigator must report the pregnancy of any female (study participant or female partner of male study participant) who becomes pregnant during investigational product treatment or within 60 days of discontinuing the investigational product (permission must be obtained from the pregnant female partner of a male patient to follow the pregnancy to conclusion and report the results). The pregnancy must be reported within 24 hours of learning of the pregnancy to the CRO using the Pregnancy Data Collection Form via the same fax and email address as for SAE reporting. The investigator should contact the designated individual(s) who receive pregnancy notification and record information related to the pregnancy on the Pregnancy Form/other designated form provided by the sponsor or its designee.

[00221] The investigator is also responsible for following the pregnancy until delivery or termination. These findings must be reported on the Pregnancy Data Collection Form and forwarded to the designated individual(s). The event meets the SAE criterion only if it results in a spontaneous abortion or a congenital anomaly.

Reporting to Regulatory Agency, Institutional Review Board/Ethics Committee and Site

[00222] The sponsor or its designee is responsible for notifying the relevant regulatory authorities and if applicable, US central institutional review board (IRB) of related, unexpected SAEs.

[00223] In addition, the sponsor or its designee is responsible for notifying active sites of all related, unexpected SAEs occurring during all interventional studies across the development program.

[00224] The investigator is responsible for notifying the local IRB, local ethics committee (EC), or the relevant local regulatory authority of all SAEs that occur at his/her site, as required. Example 1.6 - Overdose and Medication Error

[00225] Overdose or medication error of investigational product, defined below (Table 5), must be reported to the sponsor using the SAE reporting procedures outlined above whether or not they result in an AE/SAE. The 24-hour reporting period for SAEs does not apply to overdose or medication error event(s) unless the overdose or medication error event results in an SAE. Table 5: Definition of Overdose and Medication Error

Missing doses are not considered a medication error event and do not need reporting. Note that an overdose or medication error event can meet one or both of the above categories.

Example 1.7 - Safety Review Committee

[00226] A Safety Review Committee (SRC) will be involved in the conduct of this study. The SRC will be comprised of representatives from the sponsor and the study sites, including 1 medically qualified member from each participating site. The SRC has the responsibility for monitoring the clinical study’s progress and the safety of the participating subjects.

[00227] The SRC will review the cumulative safety data, PK and PD data in a dosing cohort and determine whether or not the safety data supports dose escalation to the next sequential dose level or to an intermediate dose level. The SRC may also suggest an alternate dosing regimen based on the safety, PK or PD data. Each of the 3 to 6 subjects at a dose level must have completed Cycle 1 (28-day cycle) to be eligible for the SRC review and for a decision to be made regarding subject enrollment at the next dose level. Subjects that do not complete the 28-day treatment cycle due to reasons other than DLTs will be replaced.

[00228] A safety review will be performed by the SRC to determine the RP2D of Antibody A and to begin the dose-expansion phase of the study. During the dose-expansion phase of the study, the SRC will meet regularly to review emerging safety reports and reported SAEs.

Example 1.8 - Statistics

[00229] The sample size is not based on hypothesis testing, but is appropriate for a dose escalation study in an R/R cancer patient population, designed to examine the safety, tolerability and effects of different doses of Antibody A in a population of subjects with a refractory malignancy.

[00230] This study will have the following populations of interest: the Intent-to-Treat Population includes all subjects who are enrolled and dispensed study medication at the Baseline visit; and the Safety Population includes all subjects who are enrolled and receive at least one treatment administration during this trial.

[00231] This section presents a summary of the planned statistical analyses. Additional details regarding data handling, analytical methods, and presentation of results will be provided in a Statistical Analysis Plan (SAP) for this study. The SAP will be finalized prior to database lock.

[00232] Descriptive statistics will be used to summarize the results of the trial. Continuous variables will be summarized by reporting the number of observations, mean, standard deviation, median, minimum and maximum. Categorical/discrete variables will be summarized using frequency tables showing the number and percentage of subjects within a particular category.

[00233] The disposition of all subjects enrolled in this study will be fully described with respect to their dose allocation and ultimate completion/discontinuation. Subjects who discontinue the study prematurely will be summarized by the reason for discontinuation.

[00234] All subject data will be reviewed for the occurrence of protocol deviations. Prior to database lock, all protocol deviations will be reviewed and classified with respect to the potential to influence experimental outcomes.

[00235] The analysis of demographic and baseline data will be performed for the Safety Population. Demographic variables include age, gender, race, ethnicity, height, and weight. Baseline subject characteristics to be summarized will include medical history, prior treatment for myeloma and other aspects of the subject’s myeloma, physical examination, ECG assessment, ECOG PS, and clinical laboratory tests.

[00236] Prior and concomitant medications will be summarized by dose administered and by the number and percentage of subjects taking each medication. Medications will be coded per the World Health Organization Drug Dictionary preferred term.

[00237] Exposure to investigational product will be summarized for all participating subjects. Subjects will be described with respect to cumulative exposure as well as categorized by the highest dose received. [00238] Since the investigational product will be administered via an IV infusion, compliance by subjects is not applicable.

[00239] Safety analyses will be conducted using data from the Safety Population. Safety variables include TEAEs, clinical laboratory values, vital signs, ECOG PS, physical examination, and ECG results. No formal inferential analyses will be conducted for safety variables, unless otherwise noted.

[00240] Adverse events will be coded using the most recent version of MedDRA. The incidence of TEAEs will be summarized by treatment group, SOC, and preferred term. An AE will be considered treatment emergent if it occurs after the first dose of investigational product and within 60 days after a subject’s last dose of investigational product. Similar summaries will be produced for SAEs and AEs leading to discontinuation. The intensity of AEs and the relationship to investigational product will also be summarized for each SOC and preferred term.

[00241] Descriptive summaries for all reported values and change from baseline values will be summarized by laboratory test category, treatment group, and visit.

[00242] Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, body weight, and body temperature), and ECG results will be summarized by treatment group and visit using appropriate descriptive statistics. The number and percentage of subjects with abnormal ECG findings will be summarized.

[00243] ECOG PS values will be summarized by treatment group using appropriate descriptive statistics.

[00244] All PK parameters will be described with standard summary statistics (N, mean, and standard deviation).

[00245] All efficacy measures will be described with standard summary statistics. Continuous variables will be summarized by N, the mean and standard deviation, and categorical variables will be summarized by the number and percent of subjects in each category. Time-to- event data will be summarized using the Kaplan Meier method.

[00246] The incidence of AD As will be described with standard summary statistics (N, mean, and standard deviation).

[00247] All PD parameters will be described with standard summary statistics (N, mean, and standard deviation).

[00248] No interim analysis is planned for this study. [00249] The following Table 6 provides the sequences referred to in this application.

Example 2 - Results from A Multicenter, Open-Label, Dose-Escalation Phase lb Study Of Antibody A In Subjects With Relapsed/Refractory Multiple Myeloma

[00250] Presented herein in Example 2 are certain results of the study conducted according to the methods as described in Example 1.

[00251] Two cohorts were completed in the study described in Example 1 : the 4 mg/kg and 9 mg/kg Antibody A dose cohorts in patients with relapsed/refractory multiple myeloma. There were no serious adverse events attributable to Antibody A and Antibody A was well tolerated as a single agent.

[00252] The pharmacokinetics of Antibody A were predictable and linear in the first two cohorts. The concentration of Antibody A in each patient’s serum over time, as measured in pg/mL, for Cycle 1 and part of Cycle 2 for the first two cohorts is shown in Figure 1.

[00253] The pharmacodynamics of Antibody A demonstrated a significant reduction of IL- 18 levels in the serum. The concentration of IL- 18 in each patient’s serum over time, as measured in pg/mL, for Cycle 1 and part of Cycle 2 for the first two cohorts is shown in Figure 2. The concentration of IL-18bp in each patient’s serum over time, as measured in pg/mL, for Cycle 1 and part of Cycle 2 for the first two cohorts is shown in Figure 3. The concentration of free IL- 18 in the patients’ serum can be calculated from IL- 18 and IL-18bp concentration data based on formulas known in the art.

[00254] A third cohort is currently being treated according to Example 1 : the 14mg/kg group.

[00255] The following table provides the sequences referred to in this application.

Table 6 - Table of Sequences