TW202323290A - Methods and treatment involving antibodies to il-18 - Google Patents

Abstract

The present disclosure relates to methods of treating active relapsed/ refractory multiple myeloma, optionally associated with elevated IL-18 levels, comprising administering to a human subject diagnosed with active multiple myeloma, despite prior therapy with a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, an effective amount of an anti-IL-18 antibody.

Description

Methods and treatments involving IL-18 antibodies

The present invention relates to methods of treating individuals with active relapsed/refractory (R/R) multiple myeloma (MM) by administering anti-interleukin 18 (IL-18) antibodies.

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

Multiple myeloma occurs in all races and in all geographic locations. (Cowan, AJ et al., JAMA Oncol 4:1221 (2018); Bray, F et al., CA Cancer J Clin 68:394 (2018)). Incidence varies by race; African Americans and African blacks are two to three times more likely than 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, Asians and Mexicans from Japan are at lower risk (Shirley, MH et al, Br J Haematol 163:465 (2013); Huang, SY et al, Cancer 110:896 (2007). Multiple Myeloma is also more common in men than in women (about 1.4:1). (Bray, F et al., CA Cancer J Clin 68:394 (2018)). The risk of 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 outgrowth of plasma cells producing monoclonal immunoglobulins Proliferative. (Kariyawasan, CC et al., QJM 100:635 (2007)). Plasma cells proliferate in the bone marrow and often cause bone destruction with osteolytic lesions, osteopenia, and/or pathological fractures. Multiple myeloid Tumors usually present with one or more of the following: bone pain with lytic lesions seen on conventional bone films or other imaging modalities; increased total serum protein concentration and/or presence of individual proteins in urine or serum ; unexplained anemia; symptomatic or incidental hypercalcemia; and acute renal insufficiency/failure due to concurrent immunoglobulin light chain (AL) amyloidosis. Bone marrow in most patients Contains 10% or more clonal plasma cells and ranges from less than 5% to almost 100%, with a median of 50%. (Lauby-Secretan, B et al., NEJM 375(8):794-798 (2016 )).

Increased levels of IL-18 have been associated with shortened survival in patients with MM. A group of researchers measured the levels of IL-18, vascular endothelial growth factor (VEGF), angiopoietin, TNF-α and CRP in the serum of 65 newly diagnosed myeloma patients. (Alexandrakis, MG et al., Leukemia Research 28(3):259-266 (2004)). In the study, the results showed that IL-18, VEGF, angiopoietin, TNF-α and CRP were significantly higher in stage III compared with stage II and stage I. These cytokines (measured in 27 patients) were significantly reduced after treatment. In survival analysis, higher IL-18 levels were associated with poor prognosis. The researchers concluded that increased serum IL-18 in myeloma patients was associated with advanced disease, increased levels of angiogenic interleukins, and poorer survival.

Recent studies have demonstrated that the pro-inflammatory interleukin IL-18 is closely related to the progression of pro-inflammatory disease and interference with the immune destruction of MM. (Nakamura K et al., Cancer Cell 33:634-648 (2018)). In this study, high bone marrow plasma IL-18 levels were associated with poorer overall survival in MM patients.

Embodiment 1. A method of treating active relapsed/refractory (R/R) multiple myeloma comprising administering an effective amount of an anti-IL-18 antibody to a human subject diagnosed with multiple myeloma, Wherein the anti-IL-18 antibody comprises the following six CDRs: (a) HCDR1 having the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 having the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 having the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 having the amino acid sequence of SEQ ID NO: 126; (e) LCDR2 having the amino acid sequence of SEQ ID NO: 127; and (f) LCDR3 having the amino acid sequence of SEQ ID NO: 128; (g) and Embodiment 2. wherein the individual has active multiple myeloma despite prior use of proteasome inhibitors, immunomodulators, and anti-CD38 antibody therapy; and/or Embodiment 3. wherein the individual 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 Embodiment 4. wherein the individual has an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; and/or Example 5. Where the individual has undergone prior autologous hematopoietic stem cell transplantation more than 100 days prior to the Screening Visit. Embodiment 6. The method of embodiment 1, wherein the individual is not administered an immunomodulatory drug while administering the anti-IL-18 antibody. Embodiment 7. The method as in embodiment 2, wherein the immunomodulatory drug is selected from systemic glucocorticoids, anti-TNFα antibody, anti-IL-17 antibody, anti-IL-12/23 antibody, PDE-4 inhibitor, JAK inhibitors, IL-6 inhibitors, rituximab, methotrexate, cyclosporine, and mycophenolate. Embodiment 8. The method of any one of embodiments 1 to 3, wherein the individual has elevated free or total serum or bone marrow IL-18 levels. Embodiment 9. The method according to any one of embodiments 1 to 4, wherein the serum or bone marrow IL-18 level is measured before administering the anti-IL-18 antibody. Embodiment 10. The method according to any one of embodiments 1 to 5, wherein the serum or bone marrow IL-18 level is measured after administration of the anti-IL-18 antibody, and used as a sign of therapeutic effectiveness as appropriate. Embodiment 11. The method according to any one of embodiments 1 to 6, wherein the serum or bone marrow IL-18 content is compared with the content in an individual without active R/R multiple myeloma or with a negative control Raised in comparison. Embodiment 12. The method according to any one of embodiments 1 to 7, wherein the serum or bone marrow IL-18 content is free IL-18, and the free IL-18 content is calculated as appropriate. Embodiment 13. The method according to any one of embodiments 1 to 7, wherein the serum or bone marrow IL-18 content is total IL-18. Embodiment 14. The method of any one of embodiments 1 to 8, wherein the individual has elevated free IL-18. Embodiment 15. The method of any one of embodiments 1 to 7 or 10, wherein the individual has elevated total IL-18. Example 16. A method of treating active relapsed/refractory (R/R) multiple myeloma comprising administering an effective amount of an anti-IL-18 antibody to a human subject diagnosed with multiple myeloma, and wherein the individual has elevated free or total IL-18 levels in serum or bone marrow compared to an individual without active R/R multiple myeloma or compared to a negative control, wherein the anti-IL-18 Antibodies contain the following six CDRs: (a) HCDR1 having the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 having the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 having the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 having the amino acid sequence of SEQ ID NO: 126; (e) LCDR2 having the amino acid sequence of SEQ ID NO: 127; and (f) LCDR3 having the amino acid sequence of SEQ ID NO: 128; and optionally Embodiment 17. Wherein the individual has active multiple myeloma despite prior therapy with proteasome inhibitors, immunomodulators, and anti-CD38 antibodies; and/or Example 18. wherein the individual 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 Embodiment 19. wherein the individual has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1; and/or Example 20. Where the individual has undergone prior autologous hematopoietic stem cell transplantation more than 100 days prior to the Screening Visit. Embodiment 21. The method as in embodiment 12, wherein the serum or bone marrow IL-18 level is measured before administering the anti-IL-18 antibody. Embodiment 22. The method as in embodiment 12 or 13, wherein the serum or bone marrow IL-18 level is measured after administration of the anti-IL-18 antibody, and used as a sign of therapeutic effectiveness as appropriate. Embodiment 23. The method according to any one of embodiments 12 to 14, wherein the level of free or total IL-18 in serum or bone marrow is increased compared to the level in individuals without active R/R multiple myeloma . Embodiment 24. The method according to any one of embodiments 12 to 14, wherein the serum or bone marrow IL-18 content is free IL-18, and the free IL-18 content is calculated as appropriate. Embodiment 25. The method according to any one of embodiments 12 to 14, wherein the serum or bone marrow IL-18 content is total IL-18. Embodiment 26. The method according to any one of embodiments 1 to 17, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence at least 90% identical to the entire sequence of SEQ ID NO: 121. Embodiment 27. The method according to any one of embodiments 1 to 18, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence consistent with the entire sequence of SEQ ID NO: 121. Embodiment 28. The method according to any one of embodiments 1 to 19, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence at least 90% identical to the entire sequence of SEQ ID NO: 125. Embodiment 29. The method according to any one of embodiments 1 to 20, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence consistent with the entire sequence of SEQ ID NO: 125. Embodiment 30. The method according to any one of embodiments 1 to 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 identical to that of SEQ ID NO: 121 The entire sequence is at least 90% identical, and the antibody VL domain is at least 90% identical to the entire sequence of SEQ ID NO: 125. Embodiment 31. The method according to any one of embodiments 1 to 22, wherein the anti-IL-18 antibody is administered in the form of a pharmaceutically acceptable composition. Embodiment 32. The method of any one of embodiments 1 to 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 in each 28-day treatment cycle The first day of administration. Embodiment 33. The method of any one of embodiments 1 to 24, comprising administering to the individual a dose of 10, 30, 100, 300 or 1000 mg of the anti-IL-18 antibody. Embodiment 34. The method of any one of embodiments 1 to 24, comprising administering to the individual a dose of 10 to 30 mg/kg of the anti-IL-18 antibody. Embodiment 35. The method of any one of embodiments 1 to 26, comprising administering to the individual a dose of 0.03, 0.1 or 0.3 mg/kg of the anti-IL-18 antibody. Embodiment 36. The method according to any one of embodiments 1 to 27, comprising administering to the individual the anti-IL-18 antibody at a dose of 0.01 mg/kg to 36 mg/kg. Embodiment 37. The method according to any one of embodiments 1 to 28, comprising administering to the individual the anti-IL-18 antibody at a dose of 4 mg/kg, or 9 mg/kg or 14 mg/kg. Embodiment 38. The method of any one of embodiments 1 to 29, wherein the anti-IL-18 antibody is administered intravenously. Embodiment 39. The method of any one of embodiments 1 to 30, wherein the anti-IL-18 antibody is administered subcutaneously. Embodiment 40. The method according to any one of embodiments 1 to 31, wherein the anti-IL-18 antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every six Invest once a week. Embodiment 41. The method of any one of embodiments 1-32, wherein the anti-IL-18 antibody is administered on day 1 of a 28-day treatment cycle. Embodiment 42. The method of any one of embodiments 1 to 33, comprising a dose of 4 mg/kg on day 1 of a 28-day treatment cycle, 9 mg/kg on day 1 of a 28-day treatment cycle The anti-IL-18 antibody was administered to the individual at a dose of 14 mg/kg or on day 1 of a 28-day treatment cycle. Embodiment 43. The method of any one of embodiments 1 to 34, wherein the individual is 18 years of age or older. Embodiment 44. The method of any one of embodiments 1 to 35, wherein treatment with the anti-IL-18 antibody shortens time to response (TTR) compared to standard of care therapy. Embodiment 45. The method of any one of embodiments 1 to 36, wherein treatment with the anti-IL-18 antibody prolongs progression-free survival (PFS) compared to standard-of-care therapy. Embodiment 46. The method of any one of embodiments 1-37, wherein treatment with the anti-IL-18 antibody prolongs the duration of response (DOR) compared to standard-of-care therapy. Embodiment 47. The method of any one of embodiments 1 to 38, wherein after two or more 28-day treatment cycles, according to the International Myeloma Working Group (IMWG) response guidelines, the individual A strict complete response (sCR) was achieved. Embodiment 48. The method of any one of embodiments 1 to 39, wherein the individual achieves a complete response (CR) according to IMWG response criteria after two or more 28-day treatment cycles. Embodiment 49. The method of any one of embodiments 1 to 40, wherein the individual achieves a very good partial response (VGPR) according to IMWG response criteria after two or more 28-day treatment cycles. Embodiment 50. The method of any one of embodiments 1 to 41, wherein the individual achieves a partial response (PR) according to the IMWG response criteria after two or more 28-day treatment cycles. Embodiment 51. The method of any one of embodiments 1 to 42, wherein after administering the anti-IL-18 antibody one or more times, as measured by SPEP, the individual's serum M-protein is reduced by more than Or equal to 90%. Embodiment 52. The method of any one of embodiments 1 to 42, wherein after one or more administrations of the anti-IL-18 antibody, as measured by SPEP, the individual's serum M-protein is reduced by more than Or equal to 50%. Embodiment 53. The method according to any one of embodiments 1 to 42, wherein after administering the anti-IL-18 antibody one or more times, as measured by SPEP, the individual has a reduction in serum M protein greater than or Equal to 25%, and wherein after one or more administrations of the anti-IL-18 antibody, the individual's serum M-protein is reduced by less than or equal to 49%, as measured by SPEP. Embodiment 54. The method of any one of embodiments 1 to 42, wherein after one or more administrations of the anti-IL-18 antibody, the individual has a decrease in serum M-protein as measured by SPEP. Embodiment 55. The method of any one of embodiments 1 to 46, wherein after one or more administrations of the anti-IL-18 antibody, the subject's M-protein becomes stable as measured by SPEP. Embodiment 56. The method of any one of embodiments 1 to 47, wherein the individual achieves an improvement in the Eastern Cooperative Oncology Group Performance Status (ECOG PS) score. Embodiment 57. The method of any one of embodiments 1 to 48, wherein the individual has undetectable levels of serum or bone marrow free or total IL-18 about 28 days after administration of the anti-IL-18 antibody. Embodiment 58. The method of any one of embodiments 1 to 49, wherein the individual has undetectable levels of serum or bone marrow free IL-18 about 28 days after administration of the anti-IL-18 antibody. Embodiment 59. The method of any one of embodiments 1 to 50, wherein the individual has undetectable levels of serum or bone marrow free or Total IL-18. Embodiment 60. The method of embodiments 1 to 50, wherein the individual has undetectable levels of serum free IL-18 about 112 days after administration of the anti-IL-18 antibody. Embodiment 61. The method of any one of embodiments 1 to 50, wherein the individual has reduced levels of serum or bone marrow free or total IL-18 about 28 days after administration of the anti-IL-18 antibody. Embodiment 62. The method of any one of embodiments 1 to 50, wherein the individual has a reduced level of serum or bone marrow free IL-18 about 112 days after administration of the anti-IL-18 antibody. Embodiment 63. A kit for the method of any one of embodiments 1 to 54, comprising an anti-IL-18 antibody and reagents for performing the method, optionally wherein the antibody comprises the following six CDRs: (a) HCDR1 having the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 having the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 having the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 having the amino acid sequence of SEQ ID NO: 126; (e) LCDR2 having the amino acid sequence of SEQ ID NO: 127; and (f) LCDR3 having the 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 at least 90% identical to the entire sequence of SEQ ID NO: 121, and having an amino acid sequence at least 90% identical to the entire sequence of SEQ ID NO: 125 The VL domain of the sequence.

The following definitions are provided to aid in the understanding of the present invention. These definitions are not intended to limit the invention in any way. definition

For the purposes of the present invention, "a (a/an)" entity means one or more of that entity; eg, "a cDNA" means one or more cDNAs or at least one cDNA. Accordingly, the terms "a", "one or more" and "at least one" are used interchangeably herein. It should also be noted that the terms "comprising", "including" and "having" are used interchangeably. In addition, the compound "selected from the group consisting of" refers to one or more compounds in the following list, including a mixture (ie, a combination) of two or more compounds. According to the invention, an "isolated" or "biologically pure" molecule is a compound that has been removed from its natural environment. Accordingly, the terms "isolated" and "biologically pure" do not necessarily reflect the degree to which a compound has been purified. An isolated compound of the invention may be obtained from its natural source, may be produced using laboratory synthetic techniques or may be produced by any such chemical synthetic route.

"IL-18" or "Interleukin-18" or "interferon-gamma inducing factor (interferon-gamma inducing factor)" or "IFN-ɣ-inducing factor (IFN-ɣ-inducing factor)" means IL18 gene Encoded pro-inflammatory cytokine that belongs to the IL-1 family of interkines. Like IL-1β, it is synthesized as an inactive precursor called pro-IL-18, which is activated by caspase-1 cleavage. Pro-IL-18 is present in healthy cells and is expressed constitutively by monocytes and epithelial cells. IL-18 has the function of stimulating the allergic and innate immune response.

"Elevated IL-18" as used herein means that the level of IL-18 detected in an individual is higher than normal control values. The normal control value can be determined according to the specific situation by those skilled in the art when applicable. In some cases, normal control values are industry standards agreed upon by those skilled in the art as typical levels or ranges of levels for individuals without IL-18-related pathology. In some cases, the normal control value is a reference IL-18 level from the same individual taken at one time point, and it is determined whether the individual has an elevated IL-18 level based on a sample from the same individual taken at a different (usually later) time point. High IL-18.

"Free IL-18" or "free (active) IL-18" herein refers to IL-18 in unbound form, 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-18Rα. Free IL-18 can be calculated according to known methods, eg Palladino et al. (2012) J. Neuroinflammation 9(206).

"Bound IL-18" or similar expressions thereof refer to IL-18 bound to a natural ligand, where the natural ligand is IL-18Ra or IL-18BP, as the case may be.

"Total IL-18" or similar expressions thereof refer to the total amount of free IL-18 plus bound IL-18.

"Serum" or "circulating" IL-18 is IL-18 located in serum.

"Bone marrow" IL-18 is IL-18 located in the bone marrow.

"Undetectable levels of serum IL-18" refers to levels of IL-18 below the quantitative level of an assay for measuring IL-18.

The term "antibody" is used herein 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 is required. As used herein, the term refers to a molecule comprising at least complementarity determining region (CDR) 1, CDR2 and CDR3 of the heavy chain and at least CDR1, CDR2 and CDR3 of the light chain, wherein the molecule is capable of binding to an antigen. As described herein, a "set of CDRs" includes 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 "collection of CDRs" includes HCDRs and LCDRs. The term antibody includes, but is not limited to, fragments 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 mice, cynomolgus monkeys, and the like.

The term "heavy chain" refers to a polypeptide comprising at least one heavy chain variable region, with or without a leader sequence. In some embodiments, the 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.

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

The term "light chain" refers to a polypeptide comprising at least one light chain variable region, with or without a leader sequence. In some embodiments, the light chain comprises at least a portion of the 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.

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

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

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

"Human antibody" as used herein refers to antibodies produced in humans, antibodies produced in non-human animals (such as XenoMouse®) that contain human immunoglobulin genes, and antibodies selected using in vitro methods such as phage display. An antibody, wherein the antibody repertoire is based on human immunoglobulin sequences.

The term "leader sequence" refers to a sequence of amino acid residues at the N-terminus of a polypeptide that facilitates secretion of the polypeptide from mammalian cells. The leader sequence can be cleaved upon export of the polypeptide from mammalian cells to form the mature protein. The leader sequence can be natural or synthetic, and it can be heterologous or homologous to the protein to which it is linked.

"Percent amino acid sequence identity (%)" and "homology" with respect to peptide, polypeptide, or antibody sequences are defined after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without regard to any Conservative substitutions As part of sequence identity, the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a particular peptide or polypeptide sequence. Alignment for the purpose of determining percent amino acid sequence identity can be achieved in various ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR ) software is achieved. 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.

The term "inhibition/inhibit" refers to reducing or stopping any event, such as protein ligand binding, or reducing or stopping any phenotypic characteristic, or reducing or stopping the occurrence, extent or likelihood of that characteristic. "Reduce" or "inhibit" means to decrease, reduce or arrest an activity, function and/or amount compared to a reference. Inhibition or reduction need not be complete. For example, in certain embodiments, "reduce" or "inhibit" means the ability to reduce the population by 20% or greater. In another embodiment, "reduce" or "inhibit" means the ability to reduce the population by 50% or greater. In yet another embodiment, "reduce" or "inhibit" means the ability to reduce the population by 75%, 85%, 90%, 95% or greater.

A "sample" or "individual sample" or "biological sample" generally refers to a sample that can be tested for a particular molecule. Samples may include, but are not limited to, cells, bone marrow, bodily fluids, including blood, serum, plasma, urine, saliva, feces, tears, pleural fluid, and the like.

The terms "reagent" and "test compound" are used interchangeably herein and refer to a compound, a mixture of compounds, a biological macromolecule, or a biological material such as a bacterial, plant, fungal, or animal (especially mammalian) cell or tissue of the extract. Biomacromolecules include siRNA, shRNA, antisense oligonucleotides, peptides, peptide/DNA complexes, and any nucleic acid-based molecule that exhibits the ability to modulate the activity of a SNP comprising a nucleic acid described herein or the protein it encodes.

An "individual" can be a mammal. In any of the embodiments involving an individual, the individual can be a human. In any of the embodiments involving a subject, the subject can be a cow, pig, monkey, sheep, dog, cat, fish or poultry.

As used herein, a "pediatric" subject is a human being less than 18 years of age, and an "adult" subject is 18 years of age or older.

The term "pharmaceutically acceptable composition" may refer to a composition comprising a formulation of an anti-IL-18 antibody and various pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable carrier" refers to an ingredient of a pharmaceutical formulation or composition other than the active ingredient, which is nontoxic to the individual. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers and/or preservatives.

"Treatment/treat" means both therapeutic treatment and prophylactic or preventive 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 the present invention, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, lessening of disease extent, stable disease condition (i.e., not worsening), delay or slowing of disease progression, improvement or alleviation of disease condition, and remission ( partial or complete), whether the results are detectable or not. "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.

The term "effective amount" or "therapeutically effective amount" refers to the amount of drug effective in treating a disease or condition in an individual, such as partially or completely alleviating one or more symptoms. In some embodiments, an effective amount is an amount effective to achieve the desired therapeutic or prophylactic result, at dosages and for periods of time desired.

The term "Eastern Cooperative Oncology Group Performance Status (ECOG PS) score" as used herein refers to the score as defined in Table 2 of Oken et al. (1982) Am J Clin Oncol. 5(6):649-55. An ECOG PS score of 0 means that the individual is fully active and able to maintain all premorbid physical performance without limitation. An ECOG PS score of 1 means that the individual is limited in strenuous physical activity, but able to ambulatory and able to perform light or sedentary tasks, such as light housework, office work. An ECOG PS score of 2 means that the individual is ambulatory and able to take care of themselves completely, but cannot perform any work activities; the individual is up and lasts approximately more than 50% of the waking time. An ECOG PS score of 3 means that the individual is only capable of limited self-care, with more than 50% of waking time confined to a bed or chair. An ECOG PS score of 4 means that the individual is completely disabled, unable to perform any self-care, and completely confined to a bed or chair. An ECOG PS score of 5 means death of the subject.

The term "strict complete response" or "sCR" as used herein refers to the International Myeloma Working Group (IMWG) response guidelines described in Kumar et al. (2016) Lancet Oncol. 17(8): e328-e346 defined score. It is generally defined as negative immunofixation in serum and urine, disappearance of any soft tissue plasmacytoma, and <5% plasma cells in bone marrow aspirate, plus a normal free light chain (FLC) ratio and bone marrow ascertained by immunohistochemistry. Absence of clonal cells in sections (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells).

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

The term "very good partial response" or "VGPR" as used herein refers to the score as 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 present on electrophoresis, or a ≥90% reduction in serum M-protein and urinary M-protein <100 mg/24 hours.

The term "partial response" or "PR" as used herein refers to the score as defined in the IMWG response criteria described in Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346. It is generally defined as a ≥50% reduction in serum M-protein and a ≥90% reduction in 24-hour urinary M-protein or to <200 mg/24 hours. If serum and urine M-protein is not measurable, a ≥50% reduction in the difference between affected and unaffected FLC levels is required in lieu of the M-protein criterion. If serum and urine M-protein and serum FLC assays are not measurable, a reduction in plasma cells of ≥50% is required to replace M-protein, limited by a baseline bone marrow plasma cell percentage of ≥30%. In addition to the above criteria, a ≥ 50% reduction in the size of the soft tissue plasmacytoma (the sum of the products of the largest vertical diameters (SPD) of the measured lesions) is also required, if present at baseline.

The term "time to response" or "TTR" as used herein refers to the time from initiation of treatment to the first observation of a partial or better response. TTR is limited to individuals with confirmed responses.

The term "progression-free survival" or "PFS" as used herein refers to the duration from initiation of treatment to disease progression or death, regardless of the cause of death, whichever occurs first.

The term "duration of response" or "DOR" as used herein refers to the duration from the first observation of a partial response to the time of disease progression and death from causes other than progression. The duration of each complete and partial response will be reported. DOR is limited to individuals with confirmed responses. For the purposes of calculating the DOR, as long as the response has been confirmed, the date of first observation of the response status, rather than the date of confirmation, is used as the start date.

As used herein, "relapsed/refractory" or "R/R" or "RR" multiple myeloma, including "active relapsed/refractory" multiple myeloma, refers to relapsed, refractory or relapsed aggressive and refractory multiple myeloma. As used herein, relapsed/refractory multiple myeloma refers to patients who have achieved a minimal response (MR) or better response to prior therapy become unresponsive or progress on therapy or within 60 days of prior therapy disease. Refractory disease means (1) progressive disease that progressed on previous prior therapy (progressive disease is defined in Kumar et al. (2016) Lancet Oncol. 17(8):e328–e346)); (2) stable Best disease response to previous prior therapy (stable disease is defined in Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346); or (3) Progressive disease progressing within 3 months. Recurrent disease requires fulfilling one or more of the following criteria: (1) Adding direct indicators of disease and/or end-organ dysfunction (CRAB features) associated with the underlying pure-line plasma cell proliferative disorder; it is not used Time to progression or PFS is calculated but listed as a case-by-case report or as used in clinical practice; (2) development of new soft tissue plasmacytoma or bone lesion (osteoporotic fracture does not constitute progression); (3) existing Definite increase in size of plasmacytoma or bone lesion; definite increase is defined as 50% (and ≥ 1 cm) increase as measured serially by SPD of measurable lesion; (4) hypercalcemia (> 11 mg/dL); (5) a decrease in hemoglobin ≥2 g/dL unrelated to therapy or other non-myeloid-related conditions; (6) an increase in serum creatinine of 2 mg/dL or more relative to the start of therapy and This can be attributed to myeloma; and (7) high blood viscosity associated with serum paraproteins. "Active" refers to multiple myeloma as opposed to, eg, indolent multiple myeloma. Multiple myeloma is defined, eg, in Rajkumar et al. (2014) Lancet Oncol. 15(12):e538-e548. Multiple myeloma was defined in Rajkumar et al. (2014) as either ≥10% pureline bone marrow plasma cells or biopsy-proven bone or extramedullary plasmacytoma and any one or more of the following myeloma-defining events: (1) Evidence of end-organ damage attributable to an underlying plasma cell proliferative disorder, specifically: (i) hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal, or > 2.75 mmol/L (>11 mg/dL); (ii) renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >177 μmol/L (>2 mg/dL); (iii) anemia: hemoglobin Values >20 g/L lower than the lower limit of normal, or hemoglobin values <100 g/L; (iv) Bone lesions: one or more osteolytic lesions found on skeletal radiography, CT, or PET-CT; or ( 2) Any one or more of the following malignant disease biomarkers: (i) the percentage of pure line bone marrow plasma cells ≥ 60%; (ii) the ratio of free light chains in affected serum: free light chains in unaffected serum ≥ 100; (iii) ) MRI study reveals >1 focal lesion.

"SPEP" or "serum protein electrophoresis" as used herein refers to a method used to measure proteins (also known as M proteins) in the serum of an individual.

"M-protein" or "M protein" as used herein refers to a myeloma protein, also known as a monoclonal protein, which is a type of protein antibody (or fragment thereof, such as a light chain) produced by myeloma cells. The level of this protein in serum or urine is commonly used to diagnose multiple myeloma and measure disease progression and/or response to therapy. anti -IL-18 antibody

In some embodiments, anti-IL-18 antibodies used for therapeutic purposes described herein comprise CDR sequences, and in some embodiments, comprise the variable heavy and light chains of antibody 12-GL disclosed in WO 2012/085015 region, 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 IgG1κ monoclonal antibody (mAb) that binds and neutralizes IL-18.

Antibody A inhibits the formation of IL-18/Rα/Rβ active complex in vitro and in vivo. Antibody A exhibited a high affinity of 63 pM, 6-fold higher than the natural inhibitor of IL-18 (IL-18 binding protein), and exhibited reduced Fc binding, thereby enabling highly effective anti-inflammatory effects. As a fully human antibody, Antibody A is expected to exhibit reduced anti-drug antibodies (ADA). Antibody A exhibits IL-18 neutralization and bioactivity by reducing the effect of IL-18 in various in vitro models with an IC50 at sub-nanomore concentrations, and has been shown to be effective in COPD models (by inhibiting IFN-ɣ Effective in human rhinovirus (HRV)-infected NHBE cells released from PBMCs exposed to infected NHBE medium). Antibody A has completed a 13-week IV toxicity study with no toxicity up to 100 mg/Kg per week.

In some embodiments, the anti-IL-18 antibody comprises the CDRs of antibody A: (a) HCDR1 having an amino acid sequence identical to or comprising amino acids of SEQ ID NO: 122; (b) HCDR2 having an amino acid sequence consistent with or comprising the amino acids of SEQ ID NO: 123; (c) having an amino acid sequence consistent with or comprising the amino acids of SEQ ID NO: 124 HCDR3 with an amino acid sequence; (d) LCDR1 having an amino acid sequence consistent with or comprising the amino acid of SEQ ID NO: 126; (e) having an amino group with the amino acid of SEQ ID NO: 127 and (f) LCDR3 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 128.

In some embodiments, an anti-IL-18 antibody comprises an Antibody A VH domain (SEQ ID NO: 121), which can be paired with an Antibody A VL domain (SEQ ID NO: 125), thereby forming an antibody comprising an Antibody A VH and VL domain The antibody-antigen combining site of both.

In some embodiments, anti-IL-18 antibodies are used for detection/diagnostic and therapeutic purposes as 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 individual).

In some embodiments, anti-IL-18 antibodies useful for therapeutic purposes may comprise the CDR sequences or the heavy and light chain variable regions of the antibodies disclosed in WO 2012/085015, which is incorporated herein by reference in its entirety middle. The antibodies of WO 2012/085015 mentioned 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.

Anti-IL-18 antibodies useful for therapeutic purposes may alternatively comprise 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).

Anti-IL-18 antibodies may alternatively comprise the CDR sequences or the 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 mentioned herein include the humanized anti-IL-18 antibodies mentioned in claims 1 to 7 of US 8,133,978 B2. In some embodiments, the anti-IL-18 antibody is GSK1070806, which is a humanized IgG1/κ antibody that binds to human IL-18 with high affinity (Kd=30.3 pM) and neutralizes its function. See eg Reid, P. et al., Int J Clin Pharmacol Ther. 2014 Oct;52(10):867-79. doi: 10.5414/CP202087.

In some embodiments, the anti-IL-18 antibodies of the present invention inhibit the interaction between IL-18 and IL-18 receptor (IL-18R, which includes IL-18Rα/IL-18Rβ) and IL-18BP or both. Binds and thereby reduces IL-18 activity. In some embodiments, the anti-IL-18 antibody binds to an epitope on the IL-18 molecule that completely or partially overlaps the IL-18BP binding site.

For example, an anti-IL-18 antibody can specifically bind to an epitope of IL-18 comprising residues Tyrl, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56 of human IL-18 , Pro57, Arg58, Gly59, Met60, Arg104, Ser105 and Pro107 or one or more of the corresponding residues from IL-18 from other species (eg primates such as rhesus macaques). Anti-IL-18 antibodies may bind to IL-18 epitopes comprising 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 Tyr1, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56, Pro57, Arg58, Gly59, Met60, Arg104, Ser105 and Pro107 of human IL-18.

In some embodiments, an anti-IL-18 antibody useful in the methods described herein may comprise one or more CDRs as described herein, for example comprising CDR3, and optionally also CDR1 and CDR2, to form a combination of CDRs. gather. In some embodiments, the CDR or set of CDRs is 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 a CDR or set of CDRs of any of them, or may be a variant thereof as described herein.

In some embodiments: HCDR1 can be about 7 amino acids long, comprise or consist of Kabat residues 31-35b; HCDR2 can be about 16 amino acids long, comprise or consist of Kabat residues 50-65 Composition; HCDR3 can be about 15 amino acids long, comprise or consist of Kabat residues 95-102; LCDR1 can be about 11 amino acids long, comprise or consist of Kabat residues 24-34; LCDR2 can is about 7 amino acids long, comprises or consists of Kabat residues 50-56; and/or LCDR3 can be about 9 amino acids long, comprises or consists of Kabat residues 89-97. As known in the art, in the variable region of the heavy chain, the CDRs may include the insertion of residues 31 to 35 plus two residues 35A and 35B.

In some embodiments, the anti-IL-18 antibody comprises HCDR1, HCDR2 and/or HCDR3 and/or LCDR1, LCDR2 and/or LCDR3 (CDRs belonging to individual antibodies) as provided in Table 6. Anti-IL-18 antibodies may comprise a VH as described in any of the antibodies in Table 6. Optionally, it may also comprise the VL of any of these antibodies. VL can be from the same or different antibody as VH. Also provided herein are VH domains comprising the set of HCDRs of any of the antibodies listed in Table 6 and/or VL domains comprising the set of LCDRs of any of the antibodies listed in Table 6.

In some embodiments, the anti-IL-18 antibody comprises an antibody A CDR having amino acid residue substitutions: (a) having an amino acid sequence identical to SEQ ID NO: 122 or comprising 1 relative to SEQ ID NO: 122 , HCDR1 substituted with 2 or 3 amino acid residues; (b) having an amino acid sequence consistent with SEQ ID NO: 123 or comprising 1, 2, 3 or 4 amino acids relative to SEQ ID NO: 123 HCDR2 with residue substitution; (c) HCDR3 having an amino acid sequence identical to SEQ ID NO: 124 or comprising 1, 2, 3, 4 or 5 amino acid residue substitutions relative to SEQ ID NO: 124; (d) LCDR1 having an amino acid sequence consistent with SEQ ID NO: 126 or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 126; (e) having an amino acid sequence consistent with SEQ ID NO: 126; : 127 identical amino acid sequence or LCDR2 comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 127; and (f) having an amino acid identical to SEQ ID NO: 128 The sequence or LCDR3 comprises 1, 2, 3, 4, 5, 6, 7, 8 or 9 amino acid residue substitutions relative to SEQ ID NO: 128.

In some embodiments, the anti-IL-18 antibody comprises the 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 Table 6, which have one or more substitutions within the CDRs. In some embodiments, the anti-IL-18 antibody comprises any of the antibodies listed in Table 6 with one or more substitutions within the VH and/or VL. For example, the antibody molecule of the present invention may comprise 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, Any of Antibody 11, Antibody 11_GL and Antibody A having 17, 16 or 15 or fewer substitutions within the VH and/or VL, e.g. 14, 13, 12, 11, 10, 9, 8, 7 , 6, 5, 4, 3, 2 or 1 substitution. Substitutions can potentially be made at any residue, including within sets of CDRs.

Typically, a VH domain is paired with a VL domain to provide an antibody antigen binding site, but as discussed above, either a VH or VL domain alone can be used to bind antigen. For example, an Antibody A VH domain (SEQ ID NO: 121) can be paired with an Antibody A VL domain (SEQ ID NO: 125), thereby forming an antibody antigen binding site comprising both Antibody A VH and VL domains. Similar examples are provided for the VH and VL domains of other antibodies disclosed herein.

In other embodiments, Antibody A VH is paired with a VL domain other than Antibody A VL. Light chain promiscuity is well established in the art. Likewise, the present invention also provides similar embodiments for other VH and VL domains disclosed herein. Therefore, parental antibody 1 or optimized clone 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, The VH of any of Antibody 11_GL and Antibody A can be paired with a VL domain from a different antibody, for example the VH and VL domains can be from a group selected from Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6. Different antibodies of Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL and Antibody A.

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

In some embodiments, an anti-IL-18 antibody comprises a VH domain having an amino acid sequence at least 90% identical to the entire sequence of SEQ ID NO: 121. In some embodiments, the anti-IL-18 antibody comprises a VH domain having an amino acid sequence identical to the entire sequence of SEQ ID NO: 121. In some embodiments, the anti-IL-18 antibody comprises a VL domain having an amino acid sequence at least 90% identical to the entire sequence of SEQ ID NO: 125. In some embodiments, the anti-IL-18 antibody comprises a VL domain having an amino acid sequence identical to the entire 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 sequences of the antibody VH domain and the antibody VL domain are at least 90% identical to the entire sequences of SEQ ID NO: 121 and 125.

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

In some embodiments, the anti-IL-18 antibody of the present invention comprises: a heavy chain and a light chain comprising the following complementarity determining regions (CDRs): (a) having an amino acid sequence consistent with SEQ ID NO: 129 or relative to SEQ ID NO: 129 contains 1, 2 or 3 amino acid residues substituted HCDR1; (b) has an amino acid sequence consistent with SEQ ID NO: 130 or contains 1, 2, HCDR2 substituted with 3 or 4 amino acid residues; (c) having an amino acid sequence consistent with SEQ ID NO: 131 or comprising 1, 2, 3, 4 or 5 amine groups relative to SEQ ID NO: 131 Acid residue-substituted HCDR3; (d) have an amino acid sequence consistent with SEQ ID NO: 132 or LCDR1 comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 132; ( E) has an amino acid sequence consistent with SEQ ID NO: 133 or LCDR2 comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 133; and (f) has an amino acid sequence consistent with SEQ ID NO: 133; : 134 consensus amino acid sequence or LCDR3 comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 134.

In some embodiments, the IL-18 antibody comprises an amino acid sequence identical to or comprising 1 to 12 amino acid residues relative to a heavy chain selected from the group consisting of Substituted heavy chains: SEQ ID NO: 137, SEQ ID NO: 145, and SEQ ID NO: 149; and having an amino acid sequence identical to or relative to a light chain selected from the group consisting of Light chains comprising 1 to 12 amino acid residue substituted light chains: 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 the 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.

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

In some embodiments, an anti-IL-18 antibody may lack an antibody constant region, such as a scFv.

In other embodiments, anti-IL-18 antibodies may comprise antibody constant regions. Anti-IL-18 antibodies may be whole antibodies, such as IgG, ie IgGl, IgG2 or IgG4, or may be antibody fragments or derivatives as described below. Antibody molecules can also have other formats, for example YTE in the Fc region (Dall'Acqua et al. (2002) J. Immunology , 169: 5171-5180; Dall'Acqua et al. (2006) J Biol. Chem. 281(33 ):23514-24) and/or IgG1 with TM mutation (Oganesyan et al. (2008) Acta Cryst D64:700-4).

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

For example, in some embodiments, an anti-IL-18 antibody can 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) having 15 or less (such as 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1) compared to SEQ ID NO.152 The VH domain of the sequence of amino acid replacement; 1) a VL domain of an amino acid substituted sequence; or (iii) a VH domain and a VL domain having a sequence having at least 90% sequence identity to SEQ ID NO. 152 and SEQ ID NO. 157, respectively.

Competition between anti-IL-18 antibodies can be readily assayed in vitro, e.g., using ELISA and/or by biochemical competition assays, such as labeling specific reporter molecules to an anti-IL-18 antibody so that it can be used in one or The presence of multiple other unlabeled anti-IL-18 antibodies was detected, thereby enabling the identification of anti-IL-18 antibodies binding to the same epitope or overlapping epitopes for analysis. Such methods are readily apparent to those of ordinary skill in the art and are described in some detail herein.

Variable domain amino acid sequence variants whose sequences are either of the VH and VL domains specifically disclosed herein may be used in accordance with the invention.

As described above, aspects of the invention provide an anti-IL-18 antibody comprising at least 75%, at least 80%, at least 85%, at least 90%, A VH domain with at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity, wherein the VH domain sequence is shown in the following Appendix Table 6; and/or comprising The VL domain of any one of the antibodies listed herein has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least VL domains with 99% amino acid sequence identity, wherein the VL domain sequences are shown in Table 6 below.

Aspects of the invention provide an anti-IL-18 antibody comprising a VH domain having a set of VH CDRs at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity, wherein the VH CDR sequences are shown in Appendix Table 6 and/or comprising a VL domain having a set of VL CDRs that is at least 75%, at least 80%, at least 85%, at least 90% identical to the set of VL CDRs of any of the antibodies listed herein %, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity, wherein the VL CDR sequences are shown in Appendix Table 6.

Algorithms that can be used to calculate the percent identity of two amino acid sequences are known in the art and include, for example, 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. Set parameters. Pharmaceutical formulations

Anti-IL-18 antibodies can be administered in pharmaceutically acceptable compositions. In various embodiments, compositions comprising anti-IL-18 antibodies are provided in formulations with various pharmaceutically acceptable carriers (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus , 20th Edition (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems , 7th Edition, Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients , 3rd Edition, Pharmaceutical Press ( 2000)). Various pharmaceutically acceptable carriers can be used, including vehicles, adjuvants, and diluents. In addition, various pharmaceutically acceptable auxiliary substances such as pH adjusters and buffers, tonicity adjusters, stabilizers, wetting agents and the like can also be used. Non-limiting exemplary carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.

In various embodiments, the composition comprising anti-IL-18 antibody can be obtained by dissolving, suspending or It is formulated for injection or infusion by emulsification; and, if necessary, formulated with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives. In various embodiments, the compositions can be formulated for inhalation, eg, using pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen, and the like. In various embodiments, the composition can also be formulated into sustained-release microcapsules, such as using biodegradable or non-biodegradable polymers. Non-limiting exemplary biodegradable formulations include polylactic-glycolic acid polymers. Non-limiting exemplary non-biodegradable formulations include polyglyceryl fatty acid esters. Certain methods for the preparation of such formulations are described, for example, in EP 1 125 584 A1.

Also provided are pharmaceutical packs and kits comprising one or more containers each containing one or more doses of an anti-IL-18 antibody. In some embodiments, a unit dose is provided, wherein the unit dose 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 unit doses are supplied in single-use prefilled syringes for injection. In various embodiments, the compositions contained in the unit dosage may comprise saline, sucrose or the like; buffering agents such as phosphate or the like; and/or may be formulated within a stable and effective pH range. Alternatively, in some embodiments, the composition may be provided as a lyophilized powder that can be reconstituted upon addition of an appropriate liquid, such as sterile water. In some embodiments, the composition includes one or more substances that inhibit protein aggregation, including but not limited to sucrose and arginine. In some embodiments, compositions of the invention comprise heparin and/or proteoglycans. Treatment with anti -IL-18 antibody

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

In some embodiments, the individual has active multiple myeloma despite prior therapy with proteasome inhibitors, immunomodulators, and anti-CD38 antibodies. Exemplary proteasome inhibitors include, but are not limited to, bortezomib, carfilzomib, and ixazomib. Exemplary immunomodulatory agents (IMiDs) (also known 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.

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

In some embodiments, the individual has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.

In some embodiments, the individual has undergone prior autologous hematopoietic stem cell transplantation more than 100 days prior to the Screening Visit.

In some embodiments, the individual is not administered an immunomodulatory drug concurrently with the administration of the anti-IL-18 antibody. In some embodiments, the immunomodulatory drug is selected from systemic glucocorticoids, anti-TNFα antibodies, anti-IL-17 antibodies, anti-IL-12/23 antibodies, PDE-4 inhibitors, JAK inhibitors, IL-6 inhibitors drugs, rituximab, methotrexate, cyclosporine, and mycophenolate mofetil.

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

In some embodiments, serum or bone marrow IL-18 levels are measured prior to administration of anti-IL-18 antibodies. In some embodiments, serum or bone marrow IL-18 levels are measured after administration of anti-IL-18 antibodies as a marker of therapeutic effectiveness. In some embodiments, the level of serum or bone marrow IL-18 is free IL-18. In some embodiments, the amount of free IL-18 is calculated. In some embodiments, the serum or bone marrow IL-18 level is total IL-18.

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.

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

In some embodiments, the anti-IL-18 antibody is administered weekly. In some embodiments, the anti-IL-18 antibody is administered every two weeks. In some embodiments, the anti-IL-18 antibody is administered every three weeks. In some embodiments, the anti-IL-18 antibody is administered every four weeks. In some embodiments, the anti-IL-18 antibody is administered every five weeks. In some embodiments, the anti-IL-18 antibody is administered every six weeks. In some embodiments, the anti-IL18 antibody is administered on Day 1 of a 28-day treatment cycle.

In some embodiments, the anti-IL-18 antibody is administered at a dose of 4 mg/kg on Day 1 of a 28-day treatment cycle. In some embodiments, the anti-IL-18 antibody is administered at a dose of 9 mg/kg on Day 1 of a 28-day treatment cycle. In some embodiments, the anti-IL-18 antibody is administered at a dose of 14 mg/kg on Day 1 of a 28-day treatment cycle.

In some embodiments, the individual is 18 years or older.

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

In some embodiments, the anti-IL-18 antibody is administered such that the subject achieves a strict complete response (sCR) according to International Myeloma Working Group (IMWG) response guidelines after two or more 28-day treatment cycles. In some embodiments, the anti-IL-18 antibody is administered such that the subject achieves a complete response (CR) according to IMWG response guidelines after two or more 28-day treatment cycles. In some embodiments, the anti-IL-18 antibody is administered such that the subject achieves a very good partial response (VGPR) according to IMWG response guidelines after two or more 28-day treatment cycles. In some embodiments, the anti-IL-18 antibody is administered such that after two or more 28-day treatment cycles, the subject achieves a partial response (PR) according to IMWG response guidelines. In some embodiments, administration of the anti-IL-18 antibody results in the individual achieving an improvement in Eastern Cooperative Oncology Group Performance Status (ECOG PS) score.

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 individual achieves such a score following administration of the anti-IL-18 antibody one or more times (eg, a 28-day treatment cycle). In some embodiments, the anti-IL-18 antibody is administered such that after one or more administrations of the anti-IL-18 antibody (e.g., a 28-day treatment cycle), the individual achieves the individual's serum M- Protein reduction greater than or equal to 50%. In some embodiments, the anti-IL-18 antibody is administered such that after one or more administrations of the anti-IL-18 antibody (e.g., a 28-day treatment cycle), the individual achieves the individual's serum M- A reduction in protein of greater than or equal to 25%, and wherein the subject has a reduction in serum M-protein of less than or equal to 49 as measured by SPEP following administration of the anti-IL-18 antibody one or more times (e.g., a 28-day treatment cycle) %. In some embodiments, the anti-IL-18 antibody is administered such that after one or more administrations of the anti-IL-18 antibody (e.g., a 28-day treatment cycle), the individual achieves the individual's serum M- Protein decreased. In some embodiments, following administration of the anti-IL-18 antibody one or more times (eg, a 28-day treatment cycle), the subject's M-protein becomes stable as measured by SPEP.

In some embodiments, the individual has undetectable levels of serum IL-18 about 28 days after administration of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum free IL-18 about 28 days after administration of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum IL-18 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 about 112 days after administration of the anti-IL-18 antibody. In some embodiments, the individual has reduced levels of bone marrow IL-18 about 28 days after administration of the anti-IL-18 antibody. In some embodiments, the individual has reduced levels of bone marrow IL-18 about 112 days after administration of the anti-IL-18 antibody. Free IL-18 detection analysis

Most currently available assays only measure total IL-18, which includes IL-18 bound to its receptors, including IL-18bp. Total IL-18 does not accurately reflect the amount of IL-18 that causes disease, which can be free, unbound IL-18. Therefore, where the method includes the detection of free IL-18, it may be desirable to use an assay that measures free IL-18 alone. 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 products

Any of the above methods can be practiced by a kit for detecting and/or treating conditions associated with elevated IL-18, including multiple myeloma. A kit may contain an antibody, one or more non-naturally occurring detectable labels, markers or reporters, a pharmaceutically acceptable carrier, a physiologically acceptable carrier, instructions for use, a container, an administration container, Analyze substrates or any combination thereof.

In some embodiments, the kit is used in a method of detecting IL-18 in a biological sample. It may contain anti-IL-18 antibodies and reagents for performing the method.

In some embodiments, the kit is used in a method of detecting IL-18 in a biological sample from an individual having or suspected of having multiple myeloma. It may contain anti-IL-18 antibodies and reagents for performing the method.

In some embodiments, the kit is for use in a method of detecting elevated IL-18 in a biological sample from an individual, optionally where the individual is suspected of having multiple myeloma, and also for use after diagnosis by The subject is treated by administering an effective amount of an anti-IL-18 antibody. It may contain anti-IL-18 antibodies and reagents for performing the method.

In some embodiments, a kit for use in a method of detection and/or treatment comprises a solid phase to which an anti-IL-18 antibody reagent is attached. In some embodiments, a kit for use in a method of detection and/or treatment comprises a solid phase to which IL-18 derived from a biological sample will be attached.

Solid phases for use in kits of the present invention include, but are not limited to, microtiter plates, magnetic particles, filter paper for immunochromatography, polymers such as polystyrene, glass beads, glass filters, and other insoluble supports. In one embodiment, a solid substrate containing many compartments or regions has at least one compartment coated with an antibody of the invention.

The kit of the present invention may also include another component in addition to the diagnostic agent anti-IL-18 antibody. The other components may include, but are not limited to, reagents, enzymes for labeling, their corresponding substrates, radioactive isotopes, reflective substances, fluorescent substances, colored substances, buffer solutions, and discs, as mentioned above. example

The following examples are provided to illustrate certain disclosed embodiments and should not be construed as limiting the scope of the invention 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 the amino acid sequence of SEQ ID NO: 122; NO: The heavy chain CDR of the amino acid sequence of 123; Have the heavy chain CDR of the amino acid sequence of SEQ ID NO: 124; Have the light chain CDR of the amino acid sequence of SEQ ID NO: 126; Have SEQ ID NO: a light chain CDR having an amino acid sequence of 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) comprising the amino acid sequence of SEQ ID NO: 121 and a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO: 125. Example 1 - A Multicenter, Open Label, Dose Escalation Phase 1b Study of Antibody A in Individuals with Relapsed / Refractory Multiple Myeloma Example 1.1 - Study Objectives

The primary objective of this study was to determine the recommended Phase 2 dose (RP2D) of Antibody A in individuals with relapsed/refractory (R/R) multiple myeloma. RP2D can be based on safety findings (eg, based on dose-limiting toxicity [DLT] findings), PK findings, and/or pharmacodynamic (PD) findings.

The secondary objectives of this study are: to assess the safety profile of Antibody A in R/R multiple myeloma; to assess the PK profile of Antibody A; Myeloma activity; determination of ADA incidence for Antibody A; and determination of time to response (TTR), progression free survival (PFS) and duration of response (DOR).

Exploratory objectives were to assess the effect of Antibody A on serum IL-18 levels and other inflammatory biomarkers (inflammation MAP assay) as well as IL-18 levels in bone marrow (solubilized B cell maturation antigen will be assessed at the same time points Antigen, sBCMA) content), and assess the impact of antibody A on bone marrow and peripheral blood myeloid-derived suppressor cell content. Example 1.2 - Study Design Overall Study Design and Plan

This is a multicenter, open-label, dose-escalation, arm-sequential phase 1b clinical study in individuals with R/R multiple myeloma. The trial utilized a "3+3" design. Initially, starting with an initial dose of 4 mg/kg, three subjects were enrolled at each dose. If no DLT occurs, it will be incremented to the next group. If 1 DLT occurs, the group will be expanded to 6 individuals. If no other DLT occurs, it will be escalated to the next dose. If 2 DLTs occur in the initial 3 individuals, or 2 DLTs in the expansion group of 6 individuals, the maximum tolerated dose has been exceeded and dose escalation will be stopped. Doses prior to those at which DLTs are observed will then serve as RP2Ds.

Subjects must be ≥18 years of age with active R/R multiple myeloma. Subjects must have measurable myeloma; Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; adequate hematopoietic, renal, and hepatic function; and for those who have previously undergone autologous hematopoietic stem cell transplantation Individuals, more than 100 days must have passed prior to the screening visit.

If the subject currently has an active infection requiring systemic antimicrobial therapy, has received more than 6 prior treatment regimens (for the dose expansion phase), and is within 2 weeks of using the study drug (for nitrosourea, melphalan or monoclonal antibody within 4 weeks) received corticosteroids (>10 mg/day prednisone or equivalent) or chemotherapy, had another disease within 1 year of entry into the study A malignant disease with a high probability of recurrence, suffering from any clinically significant medical condition that will interfere with the conduct of the study assessment, pregnant or breast-feeding, previously treated with anti-IL-18 antibodies, or having clinically significant abnormalities room discovery, the individual will not be eligible.

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

All subjects will undergo and have undergone adverse event (AE) monitoring and will have and have undergone a physical examination, ECOG status check, electrocardiogram (ECG) and routine safety laboratory testing to characterize the safety profile of Antibody A. Efficacy will be determined by IMWG response criteria. 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 also obtained at various time points after Antibody A administration (MAP analysis of inflammation) . sBCMA levels will be measured at the same time points. Following administration of Antibody A at selected sites, bone marrow and peripheral blood will be analyzed for the content of myeloid-derived suppressor cells.

Individuals who discontinue the study for reasons other than disease progression will require follow-up visits every 30 days until disease progression is documented or a new therapy for their disease is initiated. Once disease progression is documented or new therapy initiated, subjects will enter the survival phase of the study.

All subjects will have to come to the site for a follow-up visit 30 days after the last dose of study drug. A follow-up telephone call will be conducted 60 days after the last dose. Following the last dose of study drug, all subjects will be followed up for survival every 3 months for a period of 1 year. Follow-up therapy information and survival information will be collected via telephone contact.

Definition of Proposed Phase 2 Trial Dose

RP2D may be the dose prior to the dose at which DLT is observed. RP2D may be based on security discovery (eg, DLT-based discovery), PK discovery, and/or PD discovery.

Definition of dose-limiting toxicity

The following AEs were considered DLTs if they occurred within Cycle 1 (within 28 days of the first dose) and were considered related to Antibody A treatment: any non-hematologic AE grade ≥3; fever lasting >7 days Neutropenia or Grade 4 neutropenia; Grade 4 thrombocytopenia lasting > 7 days, or Grade 3 or 4 thrombocytopenia with clinically significant bleeding; any AE that delayed the start of Cycle 2.

Discussion of Research Design

This dose escalation study will determine the RP2D of Antibody A administered via IV infusion in individuals with R/R multiple myeloma. RP2D will be determined based on safety (DLT), PK and/or PD findings from this study. The study will use a "3+3" dose escalation design, which is a commonly used design for dose escalation studies and which minimizes exposure to subtherapeutic doses and minimizes exposure to potentially toxic, higher doses. Dose-limiting toxicities will include any Grade ≥ 3 AE for which there is no explanation other than the effect of Antibody A occurring within 28 days prior to therapy. After determining RP2D, the expansion set can be opened. inclusion criteria

Subjects must meet the following requirements to be eligible for the study: 1. Subject 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. Individual has active myeloma despite prior therapy with proteasome inhibitors, immunomodulators, and anti-CD38 antibodies. 4. The individual's ECOG PS score is 0 or 1. 5. Subject ≥ 18 years old. 6. Individuals with adequate hematopoietic, renal, and hepatic function defined as: a. Absolute neutrophil count >1,000/μL; platelet count >75,000/μL in patients with <50% bone marrow involvement b. In patients with ≥50% bone marrow involvement, absolute neutrophil count >750/μL; platelet count >50,000/μL c. Serum creatinine <2.5 mg/dL or according to the Cockcroft-Galter formula ( Cockcroft-Gault equation) calculated creatinine clearance >30 mL/min d. Aspartate transaminase/alanine transaminase <3 × upper limit of normal (ULN) and total bilirubin <2 × ULN 7. If applicable , the individual had undergone a prior autologous hematopoietic stem cell transplant more than 100 days prior to the Screening Visit. 8. Heterosexually active female patients of childbearing potential and male patients with female sexual partners of childbearing potential must agree to use effective methods of contraception (e.g. oral contraceptives; double barrier methods such as condoms and diaphragms; uterine internal device) or abstain from sexual activity during the study and for 220 days (5 half-lives) after the last dose of study drug, or abstain from sexual intercourse while participating in the study. Infertile women were women who had undergone bilateral oophorectomy or were postmenopausal (defined as the absence of menstrual cycles for 12 consecutive months). 9. Individuals have provided written informed consent for this study. exclusion criteria

The presence of any of the following criteria excluded subjects from the study: 1. Subjects currently have active infections requiring the use of systemic antimicrobial therapy. 2. Dose Expansion Phase: Subject has received more than 6 previous treatment regimens. 3. Individuals who have received corticosteroids (>10 mg/day presone or equivalent) or chemical therapy. 4. The individual suffers from hyperviscosity syndrome. 5. Individuals with myeloma involving the central nervous system, including leptomeningeal involvement. 6. Individuals judged to be at risk of imminent fracture. 7. The individual suffers from known amyloidosis or POEMS (polyneuropathy, visceral enlargement, endocrinopathy, monoclonal protein, skin changes) syndrome. 8. Individuals have suffered from another malignant disease with a high probability of recurrence within 1 year of entering the study. 9. Subject is pregnant or breastfeeding. 10. Subject has a history or positive test result of hepatitis B, untreated hepatitis C, or human immunodeficiency virus (HIV). Individuals with hepatitis C, who have received a full course of antiviral therapy, or who are currently receiving antiviral therapy and have undetectable levels of hepatitis C RNA are eligible for the trial. 11. The individual has experienced major surgery or trauma within 4 weeks of entering the study. 12. Subject has been previously treated with anti-IL-18 antibody. 13. The individual is currently taking immunomodulatory drugs, including pharmacological doses of systemic glucocorticoids (>10 mg/day presone or equivalent), anti-TNFα 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 mofetil. 14. Individuals 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. Individuals with autoimmune endocrinopathies taking stable doses of replacement hormone therapy were eligible for the trial. 15. Subject has previously undergone an allogeneic transplant. 16. The individual suffered from New York Heart Association (New York Heart Association; NYHA) class III or IV congestive heart failure (Congestive Heart Failure; CHF), myocardial infarction or acute coronary syndrome within 6 months before the screening visit; Persistent angina; severe peripheral vascular disease; or any other concurrent medical condition that may interfere with the individual's participation in the trial or interpretation of the research data. 17. The individual has mental illness, drug abuse or social conditions that would interfere with the individual's participation in or cooperation with the test requirements. 18. Subject has known allergy to any component of Antibody A. Screening failed

Individuals who do not meet the inclusion and/or exclusion criteria may be re-screened for the study with pre-approval by the medical monitor. In the case of re-screening, the first screening visit will be entered into the electronic case report form (eCRF) as a screening visit, and repeat assessments will be entered into the eCRF as an unscheduled visit. individual early exit

All subjects will be informed that they are free to withdraw from this study at any time for any reason without loss. The investigator should make every reasonable attempt to keep the individual in the study; however, if the individual withdraws consent to participate, the individual must withdraw from the study. Investigators must attempt to contact individuals who did not attend scheduled visits by telephone or other means to rule out the possibility that AEs were the reason for withdrawal. If this is the reason, the AE must be documented, reported and tracked.

The trial commissioner reserves the right to ask individuals to withdraw due to protocol deviation or other reasons.

The investigator also reserves the right to withdraw an individual from the study at any time for any reason. If an individual withdraws before completing the study, the individual will be followed up as indicated in the assessment schedule (Table 1). The reason for withdrawal must be determined by the investigator and recorded in the individual's medical records and case report form (CRF). If an individual withdraws for more than 1 reason, each reason should be documented in the source document and the most clinically relevant reason should be entered into the CRF.

Reasons for study discontinuation include, but are not limited to: • Myeloma progression • Adverse events • Need for prohibited concomitant medications • Serious protocol deviation • Investigator withdrawal in the best interest of the individual • Subject withdrawn • Lost to follow-up • Other reason. If other reasons are selected, the investigator must specify the reason in the CRF. Individual Replacement Criterion

Subjects who withdraw from the study for reasons other than DLT during the first treatment cycle may be replaced. Table 1 : Assessment Schedule filter 1st cycle _ 2nd cycle _ subsequent cycle end of study Follow up program Within 28 days of treatment day 1 _ day 2 _ day 8 _ day 15 _ day 22 _ day 1 _ day 8 _ day 15 _ day 22 _ anytime 30 days after the last dose Call 60 days after last dose Follow- ^up for progressive diseasea Overall Survival Follow-up informed consent x medical history x history of myeloma x Body checkup x Xb Xb Xb Xb vital signs ^c x x x x x x x x x x x x x ECOG PS x x x x x x x x x x x x ECG ^d x x CBC ^e x x x x x x x x x x x x x Serum chemistry test ^f x x x x x x x x x x x x x Blood coagulation test ^g x x x serum pregnancy test ^h x x urine ^analysisi x x SPEP x x x x x x x Quantitative Ig x x x x 24-hour urine M-protein ^j (UPEP) x x x x serum FLC x x x x x x x Bone marrow aspiration and ^biopsyk x x xl Skeletal ^Radiologym x x Blood sampling for PK x x x x x Xo x x Blood sampling for PD Xo x x x x Xo x x x Blood sampling for MDSC x x xl Blood sampling for anti-drug antibodies Xo Xo Xo x x Table 1 : Assessment Schedule filter 1st cycle _ 2nd cycle _ subsequent cycle end of study Follow up program Within 28 days of treatment day 1 _ day 2 _ day 8 _ day 15 _ day 22 _ day 1 _ day 8 _ day 15 _ day 22 _ anytime 30 days after the last dose Call 60 days after last dose Follow- ^up for progressive diseasea Overall Survival Follow-up Concomitant medication x x x x x x x x x x x x x Adverse event x x x x x x x x x x x x x x Administration of Antibody ^Ap x x x Survival state ^q x Note 1 : After Cycle 2 , a clinical visit is only required on the day of treatment administration ( Day 1 ) . Other clinical visits will be carried out in the third cycle and subsequent cycles according to clinical needs. Note 2 : There will be a window of ± 7 days for efficacy response assessment prior to administration of investigational product . Note 3 : Efficacy parameters ( SPEP , quantitative Ig , 24 -hour urine M- protein, and serum FLC, as appropriate ) will be assessed at Screening and during each cycle until the next scheduled dose is administered ; the last measurement will be Conducted at the end of the study. Additionally, SPEP and serum FLC will be measured on Days 15 and 22 of Cycle 1 and Day 15 of Cycle 2 . Note 4 : The window period for Day 1 , Day 2 , Day 8 , Day 15 , Day 22 of Cycle 1, any subsequent cycle visit and the end of the study visit will be ± 3 days. The window period for any follow-up visit will be ± 7 days. For bone marrow aspiration and biopsy and skeletal radiology, the window period was ± 7 days. a. Individuals who discontinue the study for reasons other than disease progression will need to be followed up every 30 days until disease progression is documented or a new therapy for their disease is initiated. Once disease progression is documented or new therapy initiated, subjects will enter the survival phase of the study. b. Targeted physical examination focused on areas of myeloma involvement or adverse events. c. Vital signs include pulse, blood pressure, respiration rate, temperature, and weight. d. ECGs will be performed at Screening, Cycle 1 Day 1, and thereafter as needed. e. CBC includes WBC count, differential count, HGB count, HCT count, platelet count. f. Serum chemistry tests including sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, calcium, magnesium, phosphorus, uric acid, total protein, albumin . g. Coagulation function tests include PTT and INR. h. Serum pregnancy test for women of reproductive age. i. Urine sample analysis includes pH value, specific gravity and test strips for protein, blood, glucose and ketone. j. If there is no measurable serum M-protein, collect 24-hour urine for M-protein measurement. k. Bone marrow aspiration and biopsy will be performed at the time of screening, on the first day of the second cycle, and when complete response or strict complete response is confirmed. l. On Day 1 of Cycle 3 only. m. Radiology for bone lesions may include skeletal examination, CT/PET, or MRI and should only be repeated to document response. n. Samples should be obtained ±1 hour after the end of the infusion. o. Prior to drug administration. p. The investigational product will be administered on Day 1 of each 28-day treatment cycle until disease progression or toxicity. Table 1 : Assessment Schedule filter 1st cycle _ 2nd cycle _ subsequent cycle end of study Follow up program Within 28 days of treatment day 1 _ day 2 _ day 8 _ day 15 _ day 22 _ day 1 _ day 8 _ day 15 _ day 22 _ anytime 30 days after the last dose Call 60 days after last dose Follow- ^up for progressive diseasea Overall Survival Follow-up q. Following the last dose of study drug, all subjects will be followed up for survival every 3 months for a period of 1 year. Follow-up therapy information and survival information will be collected via telephone contact. Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood urea nitrogen; CBC=complete blood count; CT=computed tomography; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance status; FLC = free light chain; HCT = hematocrit; HGB = hemoglobin; Ig = immunoglobulin; INR = international normalized ratio; MDSC = myeloid-derived suppressor cells; MRI = magnetic resonance imaging; PET = positron emission Tomography; PD = pharmacodynamics; PK = pharmacokinetics; PTT = partial thromboplastin time; SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis; WBC = white blood cells. Example 1.3 - Therapeutic Identification Study Products, Dose and Mode of Administration

Antibody A is supplied as a lyophilized powder in a 3 mL single-use glass vial. Each vial contained 50 mg of Antibody A and was reconstituted with 1.2 mL of Water for Injection. An appropriate amount of reconstituted Antibody A was then diluted in saline and infused over 1 hour. Administer 4 mg/kg (maximum dose 300 mg), 9 mg/kg (no change from previous) or 14 mg/kg (maximum dose 1000 mg ; relative to the previous unchanged) dose of Antibody A until disease progression or toxicity. Intermediate doses may also be explored based on SRC recommendations. give it treatment

Eligible individuals will receive 4 mg/kg (maximum dose 300 mg), 9 mg/kg (no change from previous), or 14 mg/kg via 1-hour intravenous infusion on Day 1 of each 28-day treatment cycle (maximum dose 1000 mg; no change from previous) doses of Antibody A until disease progression or toxicity. Blinded and Unblinded Treatment Allocation

This is an open label study. Dose selection in studies

This study will use doses of 4, 9 and 14 mg/kg administered on Day 1 of each 28-day treatment cycle. Dose Adjustment Guidelines

Dose adjustments for individual subjects are not planned in this study. previous therapy

Prior therapy included all treatments received within 28 days of the first dose day of the study product. Concomitant therapy

Concomitant therapy refers to all therapies taken between the date of the first dose of the investigational product and the end of the follow-up period (inclusive). Concomitant therapy information must be recorded on the appropriate CRF page. licensed therapy

Patients were treated for all episodic medical conditions at the discretion of the investigator according to community medical standards of care. Individuals receive treatment to relieve symptoms associated with myeloma, such as analgesics (opioid and non-opioid analgesics), antibiotics, blood transfusions, and the like. Patients may receive denosumab or other bone preparations as long as they have taken such agents for at least 3 months prior to Study Day 1 (discussed with medical monitor as needed). Inhaled bronchodilators are permitted if needed. It is at the investigator's discretion to administer antibiotics and OTC medications deemed necessary for the individual's welfare.

The vaccination status of the individual should be reviewed prior to study initiation according to current immunization guidelines and it is recommended to avoid vaccination within 4 weeks of initiating Antibody A treatment. forbidden therapy

Any therapy designed to treat an individual's underlying myeloma was prohibited during the trial. Individuals who need to undergo palliative radiation may be permitted to undergo this treatment after discussion with the trial sponsor's medical monitor.

During the study period, initiation of new investigational compounds was prohibited.

The use of immunomodulatory drugs is prohibited. Immunomodulatory drugs include pharmacological doses of systemic glucocorticoids (>10 mg/day presone or equivalent), anti-TNFα antibodies, anti-IL-17 antibodies, anti-IL-12/23 antibodies, PDE-4 inhibitors agents, JAK inhibitors, IL-6 inhibitors, rituximab, methotrexate, cyclosporine, mycophenolate mofetil. Intranasal, intraocular, inhaled, and intraarticular glucocorticoids are allowed.

Individuals who received excluded therapies during the study may not be eligible to continue the study, at the discretion of the trial sponsor. Post-study treatment

Following study discontinuation, subjects may be treated at the discretion of the investigator. Example 1.4 - Study Procedures Study Duration

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 visits, subjects will be contacted for safety assessments 60 days after the last dose of study product. Following the last dose of study product, survival follow-up will be performed every 3 months for a 1-year period. safety assessment

Safety and tolerability assessments will include assessment of AE frequency and severity and changes in clinical laboratory values, vital signs, ECG records, ECOG PS scores, and physical examination findings. Clinical laboratory tests to be performed

Samples for the following clinical laboratory tests will be collected at the time points specified in the assessment schedule (Table 1).

Blood tests include hemoglobin, hematocrit, platelet count (or estimate), and white blood cell count (including differential count).

Serum chemistry tests include albumin, total bilirubin, total protein, calcium, alkaline phosphatase, alanine transaminase, aspartate transaminase, blood urea nitrogen, creatinine, magnesium, glucose, sodium, potassium, Chloride, bicarbonate, phosphorus and uric acid.

Coagulation tests will include partial thromboplastin time and international normalized ratio.

Serum pregnancy tests will be administered to women of childbearing age.

Urinalysis tests include pH, specific gravity, and dipstick for protein, blood, glucose, and ketones; and microscopic examination if blood or protein is 2+ or higher.

Laboratory samples will be analyzed at the local laboratory facility according to its collection and handling requirements. Sampled blood volume

The blood volumes sampled in the first two cycles in this study are shown in Table 2. Table 2 : Sampled blood volume per individual type Volume of each sample Sample serial number Total serum chemistry test 3.5mL 9 31.5 mL complete blood count 2mL 9 18mL pharmacokinetics 2mL 7 14mL Pharmacodynamics 4.5mL 7 31.5 mL MDSC 5mL 3 15mL anti-drug antibodies 2mL 2 4mL SPEP 3mL 5 15mL FLC 4mL 5 20mL Quantitative Ig 5mL 2 10mL total ( maximum amount ) 159mL NOTE: These sample blood volumes are for Screening and first two cycles only. Abbreviations: FLC = free light chain; MDSC = myeloid-derived suppressor cells; SPEP = serum protein electrophoresis. Evaluation of Laboratory Values

Normal ranges for values used for laboratory assessment in this study will be provided by the local laboratory agency. These ranges will be considered as reference ranges for making decisions on specific positions.

If a laboratory value is outside the reference range, it may not be clinically relevant. Investigators must evaluate out-of-range values and document their assessment of clinical relevance in individual source files. Abnormal laboratory values may be considered AEs if they are clinically significant; if they require intervention; or if they alter the administration of study drug.

All laboratory values showing clinically relevant or pathological changes in the opinion of the Investigator during or after treatment termination will be discussed with the medical monitor as needed and reported as AEs and followed up. Clinical Examination: Vital Signs

Blood pressure, pulse rate, respiration rate, body temperature and body weight will be measured at the times specified in the assessment schedule (Table 1). Additional blood pressure and pulse rate measurements may be taken at the investigator's discretion to ensure proper monitoring of individual safety and accurate recording of vital sign measurements. Any change from baseline that the investigator considers clinically meaningful is recorded as an AE. Clinical Examination: Electrocardiogram

A standard 12-lead ECG will be taken after the individual has been lying on their back for about 5 minutes. All ECG recordings will be identified by the individual number, date and time of the recording and a copy will be included in the individual's source file.

A 12-lead ECG will be performed at Screening, Cycle 1 Day 1, and subsequent periods as needed. ECGs performed within 6 months of Screening will be accepted as long as no new cardiac symptoms or events occur (Table 1). All ECG values showing clinically relevant or pathological changes in the opinion of the investigator during treatment or after treatment termination will be discussed with the medical monitor and reported as AEs and followed up. Clinical Examination: Physical Examination

A complete physical examination will be performed at the Screening Visit prior to possible exposure to the study product and at the end of the study (Table 1). In addition, targeted physical examinations focusing on areas of myeloma involvement or AEs will be performed during treatment administration. Any clinically significant physical examination findings should be reported and reported as AEs and followed up.

Clinical examination: ECOG performance status

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 individual's ability to perform daily living. Clinical Examination: Adverse Events

The investigator is responsible for detecting and recording events that meet the criteria and definitions of AE or SAE described previously. At each visit, individuals will be allowed time to spontaneously report any concerns since the last visit or assessment.

Any clinically relevant observation that occurs during the visit will also be considered an AE.

pharmacokinetics

Blood will be drawn for PK analysis according to Table 1.

Serum Antibody A concentrations in serum samples will be analyzed by a validated method.

Pharmacokinetic indicators may include, but are not limited to, estimates of C _max , t _1/2 , CL, volume of distribution (V _d ), and area under the concentration-time curve (AUC _{0 → t} ) from time 0 to time t. effect

Efficacy will be assessed by the procedure described in the following subsections and graded according to the IMWG response criteria outlined in Table 3 (Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346). All multiple myeloma disease assessments outlined below will need to be performed at the study visits specified in Table 1, and investigators should make every effort to collect all multiple myeloma disease assessments at each time point. Response assessments will be performed during each cycle with a window period to allow for disease status assessments before the next scheduled dose is administered.

Two consecutive assessments were required to confirm response (Table 3). For individuals who achieve a complete response (CR) or a strict complete response (sCR), samples for confirmation using serum protein immunofixation, quantification of Ig, and serum FLC for serum protein electrophoresis (SPEP) must be collected in duplicate at the time of reaction, And this duplicate sample must be provided to the local laboratory institution. Table 3 : IMWG Response Guidelines React Subcategories response criterion ^a Strict complete response (sCR) CR plus normal FLC ^ratiob as defined below, and absence of clonal cells in bone marrow sections as determined by immunohistochemistry (for κ and λ patients, after counting > 100 plasma cells ^c , κ/λ ratios, respectively ≤4:1 or ≥1:2) complete response (CR) Negative immunofixation in serum and urine, disappearance of any soft tissue plasmacytoma, and <5% plasma cells in bone marrow aspirate Very good partial response (VGPR) Serum and urine M-protein detectable by immunofixation but not present on electrophoresis, or serum M-protein reduction ≥90% and urine M-protein content <100 mg/24 hours Partial Response (PR) Serum M-protein decreased by ≥50%, and 24-hour urine M-protein decreased by ≥90% or reduced to <200 mg/24 hours. If serum and urine M-protein is not measurable, a ≥50% reduction in the difference between affected and unaffected FLC levels is required in lieu of the M-protein criterion. If serum and urine M-protein and serum FLC assays are not measurable, a reduction in plasma cells of ≥50% is required to replace M-protein, limited by a baseline bone marrow plasma cell percentage of ≥30%. In addition to the above criteria, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required if present at baseline. ^d Minimal Response (MR) Serum M-protein was reduced by ≥25% but <49%, and 24-hour urine M-protein was reduced by 50% to 89%. In addition to the above criteria, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required if present at baseline. ^d Stable disease (SD) Not recommended for use as an indicator of response; stability of disease is best described by providing an estimate of time to progression. Does not meet criteria for CR, VGPR, PR, MR or PD. Progressive disease (PD) ^e,f Any one or more of the following criteria: 25% increase relative to the lowest confirmed response value in one or more of the following criteria: Absolute increase in serum M-protein ≥ 0.5 g/dL; if the lowest M-group If the score is ≥5 g/dL, the serum M-protein will increase by ≥1 g/dL; Urinary M-protein (the absolute increase must be ≥200 mg/24 hours); In patients: difference between affected and unaffected FLC levels (absolute increase must be >10 mg/dL); in patients with unmeasurable serum and urine M-protein levels and unmeasurable affected FLC levels: vs. baseline Percentage of bone marrow plasma cells regardless of status (absolute increase must be ≥10%); new lesion, >1 lesion with SPD ^d increased by ≥50% relative to nadir, or longest diameter increase of previous lesion >1 cm in short axis 50%; ≥50% increase in circulating plasma cells if circulating plasma cells are the only measure of disease (minimum 200 cells/µl) Clinical recurrence Clinical relapse requires fulfillment of one or more of the following criteria: Increase in direct indicators of disease and/or end organ dysfunction (CRAB features) associated with the underlying homologous plasma cell proliferative disorder. It is not used to calculate time to progression or PFS, but is listed as a case-by-case report or as used in clinical practice; Development of new soft tissue plasmacytoma or bone lesion (osteoporotic fracture does not constitute progression); Existing plasmacytoma Cell tumors or bony lesions clearly increased in size. Definite enlargement was defined as 50% (and ≥1 cm) enlargement as measured serially by SPD ^f of measurable lesions; hypercalcemia (>11 mg/dL); associated with therapy or other non-myeloid-related disease Decrease in hemoglobin ≥2 g/dL unrelated to symptoms; Elevation in serum creatinine of 2 mg/dL or more relative to start of treatment and attributable to myeloma; Hyperviscosity associated with serum paraproteins Source: Kumar et al. (2016) Lancet Oncol. 17(8):e328-e346. Abbreviations: ASCT = autologous stem cell transplantation; CR = complete response; CRAB features = elevated calcium, renal failure, anemia, osteolytic lesions; CT = computed tomography; DOR = duration of response; FDG = fluorodeoxygen 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 = strict complete response; SD = stable disease; SPD = largest vertical diameter of the lesion measured sum of products; VGPR = very good partial response. ^aAll response categories required 2 consecutive assessments at any time prior to initiation of any new therapy. ^bAll recommendations for clinical use in relation to serum FLC levels or FLC ratios are based on results obtained using the validated Freelite test (Binding Site, Birmingham, United Kingdom). ^c Immunohistochemical determination of the presence/absence of clonal cell lines is based on the kappa/lambda/L ratio. Abnormal κ/λ ratios determined by immunohistochemistry require a minimum of 100 plasma cells for analysis. The abnormal ratio reflecting the presence of abnormal pure abo is κ/λ>4:1 or <1:2. dPlasmacytoma measurements should be obtained from the CT portion ^of PET/CT or MRI scans or dedicated CT scans, when applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurements of tumor size will be determined by SPD. ^ePositive immunofixation occurring only in patients previously classified as achieving CR will not be considered progression. For the purposes of calculating time to progression and PFS, patients who have achieved CR and are MRD negative should be evaluated using the criteria listed for PD. ^f In cases where a value is considered to be a spurious result in the investigator's judgment (eg possible laboratory error), this value will not be considered in determining the minimum value. SPEP

SPEP with quantification of individual protein bands (M-spike protein) and immunofixation of serum proteins will be performed to assess response. UPEP

Urine protein electrophoresis (UPEP; 24-hour urine) using M-spike protein quantification and urine protein immunofixation will be performed to assess the response of individuals without M-spike protein on SPEP.

Quantitative immunoglobulin content

Quantitative Ig content will be obtained if SPEP is considered unreliable for routine M-protein measurements (eg, patients with immunoglobulin A or immunoglobulin D myeloma).

Serum FLC will be performed to assess the response of patients whose serum FLC expresses the patient's myeloma protein.

skeletal examination

A baseline skeletal examination will be performed using X-rays and/or other clinically appropriate imaging modalities such as Magnetic Resonance Imaging [MRI], Whole Body Computed Tomography [CT] or Positron Emission Tomography [PET]/CT, This will be determined by the investigator.

Skeletal examination should include lateral radiographs of the skull, anterior-posterior and lateral views of the spine, and anteroposterior views of the pelvis, ribs, femur, and humerus.

If osteolytic lesions or plasmacytomas were observed at baseline, their number and size should be recorded in the eCRF. Follow-up assessments for bone lesions and/or plasmacytomas are only required to document response or progression.

In individuals without soft tissue plasmacytoma (ie, only bone lesions), a skeletal examination should be performed by X-ray or low-dose CT. Contrast imaging is not required.

In individuals with soft tissue plasmacytoma, a skeletal examination should be performed by X-ray or low-dose CT (contrast contrast is not required) and in addition, MRI or CT or PET/CT usually requiring contrast enhancement should be performed.

Bone marrow aspirate and biopsy

Bone marrow aspirates were collected at screening to confirm the diagnosis of multiple myeloma. Following initiation of study treatment, bone marrow aspirate will be collected according to Table 1.

Patients who achieved CR or sCR required bone marrow aspirate at the time of response unless sample collection and/or processing was deemed not feasible after consultation with the medical monitor.

A portion of the bone marrow aspirate collected at the time of reaction and a slide of the bone marrow biopsy were provided to the local laboratory.

Bone marrow aspiration may also be performed to assess progression as clinically indicated. Immunogenicity

Blood will be drawn for immunogenicity analysis according to Table 1. Details of immunogenic sample collection and handling can be found in the study site and/or research laboratory manual. Serum samples will be analyzed by a validated method for ADA determination. The incidence of ADA against Antibody A will be determined.

Pharmacodynamics

PD will be determined by measuring serum IL-18 levels and other inflammatory markers (MAP analysis of inflammation) obtained at various time points after antibody A administration (Table 1). sBCMA levels will be measured at the same time points.

At the times mentioned in the assessment schedule (Table 1 ), the content of bone marrow and peripheral blood myeloid-derived suppressor cells after the administration of Antibody A will be analyzed. Example 1.5 - Adverse Event Adverse Event Collection

An AE is defined as any adverse medical event that occurs in a patient or clinical study subject administered a medicinal product that does not necessarily have a causal relationship with the product. Thus, an AE can be any adverse and unexpected sign (including a new, clinically important abnormal laboratory finding), symptom, or disease temporally related to the product, whether related to the product or not. An AE will be considered treatment-emergent if it occurs after the first dose of investigational product and within 60 days of the subject's last dose of investigational product.

All AEs from the time of administration of the first dose (Cycle 1, Day 1) to the 60-day follow-up period (Table 1) were collected. This includes events that occurred during the study screening period, regardless of whether the study product was administered. When possible, diagnoses should be recorded rather than symptom lists. If no diagnosis has been made, each symptom should be listed individually. All AEs shall be documented on the appropriate AE pages in the eCRF and in the source documents.

All adverse events must be followed to closure (subject's health has returned to its baseline state or all variables have returned to normal), regardless of whether the subject remains in the study. Closing indicates achievement of the outcome, stabilization (the investigator does not anticipate any further improvement or deterioration of the event), or an alternative explanation for the event. As appropriate, medical tests and examinations are performed so that resolution of the event can be documented. Severity of Adverse Events

The severity of AEs will be based on the Common Terminology Guidelines 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. Events with a change in severity shall be recorded as new events. Exacerbations of pre-treatment events after initial administration of investigational product must be recorded as new AEs. For example, if an individual experiences mild intermittent headaches prior to administration of the investigational product; but the headache intensity increases to moderate after the first dose of the investigational product, a new AE, Moderate intermittent headaches. For events not listed in CTCAE, severity will be determined using the following definitions. Mild is defined as usually transient and may require only minimal treatment or therapeutic intervention; events generally do not interfere with daily activities of daily living. Moderate is defined as usually relieved by additional specific therapeutic intervention; the event interferes with daily activities of daily living, causing discomfort, but without risk of significant or permanent harm to the individual. Severe is defined as disruption of daily activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Life-threatening is defined as an individual who is in immediate danger of death at the time of the event. Fatal is defined as an event resulting in the death of an individual.

Distinguishing serious AEs from SAEs is critical. Severity is a classification of intensity, and SAE is an AE that meets the severity criteria. Relationship Classification

The physician-researcher must assess the relationship of each AE to the investigational product. Investigators should use their medical judgment to determine whether there is a reasonable possibility that the event may have been caused by the investigational product. If there is no legitimate reason to suggest a relationship, the AE should be classified as "unrelated". Otherwise, AEs should be classified according to the following guidelines. Causality assessments must be documented in source documents and in the eCRF (Table 4). Table 4 : Assessment of relationship to study product relation describe irrelevant Not exposed to study product. Or there is no reasonable correlation between the administration of the investigational product and the timing of the AE. Or the AE is considered to be possibly related to an etiology other than the use of the investigational product, i.e. there is no fact/evidence or argument to suggest a causal relationship to the investigational product. may be related There is a reasonable correlation between the timing of the administration and research product and the appearance of the AE. and AEs that were not equally adequately explained by factors or causes other than exposure to the investigational product. very likely related There is a reasonable correlation between the timing of the administration and research product and the appearance of the AE. And AEs were more likely to be explained by exposure to the study product than other factors or causes. AE = adverse event. The result of the last observation

Results at last observation are to be classified as: recovering/resolving; recovering/resolving with sequelae; recovering/resolving; not recovering/not resolving; fatal; or unknown. Reporting of Serious Adverse Events

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 first noticing the SAE. The investigator or designee must complete the appropriate SAE form, sign and date it, and verify the accuracy of the information against the corresponding source document. This information should be sent to the CRO Pharmacovigilance Unit. serious adverse event definition

A SAE is any adverse medical event, whether considered related or not, at any dose that: results in death; is life-threatening; requires hospitalization or prolongs existing hospitalization; results in persistent or significant disability/incompetence; Congenital abnormality; or important medical event.

It should be noted that the term "life-threatening" in the definition of "serious" refers to an event in which the individual is at risk of death if the event occurs; it does not refer to an event that is hypothetically likely to result in death if the event becomes severe.

It should be noted that hospitalization was defined as a 24-hour stay in a hospital or an overnight stay. Elective hospitalization for the treatment of a condition that existed prior to exposure to the test drug, or for the diagnostic evaluation of an AE, does not qualify as a SAE for that condition or event. Additionally, an overnight stay in a hospital solely due to transportation, organizational or accommodation issues and without a medical background is not considered a SAE.

It should be noted that congenital anomalies in infants born to mothers exposed to the investigational product during pregnancy are SAEs. However, a newly diagnosed pregnancy in an individual receiving the investigational product is not considered an SAE unless the investigational product is suspected of interacting with the contraceptive method and resulting in pregnancy.

It should be noted that medical and scientific judgment should be exercised in deciding whether it is appropriate to consider other conditions as serious, such as may not be immediately life-threatening or result in death or hospitalization, but may place the individual at risk or may require intervention to prevent the above A major medical event with one of the other outcomes listed in the definition. Examples of such events are intensive treatment in the emergency room or at home for allergic bronchospasm, dyscrasias or convulsions that do not result in hospitalization, or development of drug dependence or substance abuse. Serious adverse event collection time frame

All SAEs, regardless of relationship to the study, were collected from the time the subject signed the informed consent until the time of the subject's last visit (office or telephone contact). The investigator or designee must promptly report all SAEs to the CRO within 24 hours of first noticing the event.

Any SAE discovered by the investigator at any time interval after study completion must be reported to the CRO within 24 hours of first noticing the event, regardless of relationship to the study. Occurrence and resolution date of serious adverse events

The date of occurrence of the SAE was defined as the date on which the event met the severity criteria. The resolution date is the date on which the event no longer meets the severity criteria, symptoms resolve, or the event is considered chronic. In the case of hospitalization, the date of hospitalization and date of discharge were considered as the date of onset and date of resolution of the SAE, respectively.

Any sign or symptom experienced by the subject after signing the informed consent form, or before the date of SAE occurrence, or after the date of SAE resolution must be recorded as an AE. fatal result

Fatal was designated as an outcome only if the AE caused death. If more than 1 AE could be related to the individual's death, a death outcome should be indicated for each such AE.

Any AE that resulted in the death of the subject had to undergo a fatal examination as a result, with the date of death recorded as the date of resolution. If not so reported, AEs resulting in death must be reported as SAEs within 24 hours.

For other AEs that persisted at the time of death and did not result in the death of the subject, the results should be considered non-resolving and no resolution date recorded. Adverse events of special concern

The following events will be considered AEs of particular interest during the study: immunosuppression (decreased white blood cell count, thrombocytopenia, anemia) and increased tumor frequency. Pregnant

All females of reproductive age participating in research should be provided with advice regarding the need to practice appropriate contraceptive measures and the importance of avoiding pregnancy during research participation. Women should be instructed to contact the Investigator or Investigator immediately if they become pregnant or suspect pregnancy.

At screening and at the end of the study, each woman will take a pregnancy test. Women who are found to be pregnant at screening will be excluded from the study and will be considered screening failures. Women who are found to be pregnant after dosing will be required to discontinue the study and complete the study visit assessment as soon as possible after pregnancy is learned.

The investigator must report the pregnancy of any woman (study participant or female spouse of a male study participant) who becomes pregnant during study product treatment or within 60 days of discontinuation of study product (permission must be obtained from the pregnant female spouse of a male patient to track pregnancy to draw conclusions and report results). Pregnancy must be reported to the CRO within 24 hours of knowing the pregnancy using the Pregnancy Data Collection Form via the same fax and email address as the SAE report. The investigator should contact the designated individual who received the notification of pregnancy, and record information about the pregnancy on the pregnancy form/other designated form provided by the test commissioner or his designee.

Investigators are also responsible for following pregnancies until delivery or termination of pregnancy. These findings must be reported on the pregnancy data collection form and forwarded to the designated individual. The event complies with SAE guidelines only if it results in a spontaneous abortion or congenital anomaly. Reporting to governing bodies, institutional review boards / ethics committees, and study sites

The trial sponsor or its designee is responsible for notifying relevant regulatory agencies and, if applicable, the US Central Institutional Review Board (IRB) of relevant unexpected SAEs.

In addition, the trial commissioner or its designee is also responsible for notifying the active study site of all relevant, unexpected SAEs occurring during all intervention studies throughout the development program.

Investigators are responsible for notifying the local IRB, local ethics committee (EC) or relevant local governing body of all SAEs occurring at their study site, as appropriate. Example 1.6 - Overdose and Medication Errors

Overdoses or medication errors of investigational products as defined below (Table 5) must be reported to the trial sponsor using the SAE reporting procedure outlined above, regardless of whether they cause an AE/SAE. The 24-hour reporting period for SAEs does not apply to overdose or medication error events unless the overdose or medication error event caused the SAE. Table 5 : Definitions of Overdose and Medication Errors category definition drug overdose Intentional or unintentional ingestion of investigational product in doses exceeding the prescribed individual dose as part of a clinical trial. medication error Errors in prescribing, dispensing, administering, and/or using the investigational product. Medication errors may be reported to the trial sponsor or their designee if they involve: Assigning, administering, and/or using non-assigned treatment (eg, individual use of an inappropriate study product package). Allocate, administer and/or use expired investigational products. Missed doses are not considered medication error events and do not need to be reported. It should be noted that events of overdose or medication error may meet one or both of the above categories. Example 1.7 - Security Review Board

A Safety Review Committee (SRC) will participate in the conduct of this study. The SRC will include representatives from the trial sponsor and the study sites, including 1 qualified medical member from each participating study site. SRC is responsible for monitoring the progress of clinical research and the safety of participating individuals.

The SRC will review the cumulative safety data, PK and PD data in the dosing group and determine whether the safety data support dose escalation to the next consecutive dose level or an intermediate dose level. SRC can also propose alternative dosing regimens based on safety, PK or PD data. Three to six subjects at one dose level must each complete Cycle 1 (28-day cycle) to be eligible for SRC review and decision on subject enrollment for the next dose level. Individuals who do not complete the 28-day treatment cycle for reasons other than DLT will be replaced.

A safety review will be conducted by the SRC to determine the RP2D of Antibody A and begin the dose expansion phase of the study. During the dose expansion phase of the study, the SRC will meet periodically to review emerging safety reports and reported SAEs. Example 1.8 - Statistics

The sample size was not based on hypothesis testing but was suitable for a dose escalation study in the R/R cancer patient population designed to examine the safety, tolerance, and Receptivity and effect.

The study will have the following populations of interest: the intention-to-treat population includes all individuals who are enrolled at the Baseline Visit and are assigned study drug; and the safety population includes all individuals who are enrolled during the trial and receive at least one treatment administration.

This section presents an overview of the planned statistical analysis. Additional details on data processing, analysis methods and presentation of results will be provided in the Statistical Analysis Plan (SAP) for this study. SAP will finalize before the database is locked.

Descriptive statistics will be used to summarize the results of the trials. Continuous variables will be summarized in terms of number of reported observations, mean, standard deviation, median, minimum and maximum. Categorical/discrete variables will be summarized using a frequency table showing the number and percentage of individuals within a particular class.

The disposition of all subjects enrolled in this study will be fully described with respect to their dose allocation and eventual completion/discontinuation. Individuals who discontinued the study early will be outlined according to the reason for discontinuation.

All individual data will be reviewed for the occurrence of protocol deviations. Prior to database lock, all protocol deviations will be reviewed and categorized according to their likelihood of affecting experimental results.

Demographic and baseline data analyzes will be performed on the safety population. Demographic variables included age, sex, race, ethnicity, height and weight. Baseline individual characteristics to be summarized will include medical history, previous treatment for myeloma and other aspects of the individual's myeloma, physical examination, ECG evaluation, ECOG PS, and clinical laboratory tests.

Prior and concomitant medications will be summarized by dose administered and the number and percentage of subjects taking each drug. Drugs will be coded according to the WHO Drug Dictionary preferred terms.

The study product exposures of all participating individuals will be summarized. Individuals will be described with respect to cumulative exposure and classified according to the highest dose received.

Individual compliance does not apply as the study product will be administered via IV infusion.

Safety analyzes will be performed using data from the safety community. Safety variables included TEAEs, clinical laboratory values, vital signs, ECOG PS, physical examination, and ECG results. Formal inferential analyzes will not be performed on safety variables unless otherwise indicated.

Adverse events will be coded using the latest version of MedDRA. The incidence of TEAEs will be summarized by treatment group, SOC, and preferred term. An AE was considered treatment-emergent if it occurred after the first dose of investigational product and within 60 days after the subject's last dose of investigational product. A similar overview will be generated for SAEs and AEs that cause outages. AE strength and relationship to study product will also be outlined for each SOC and preferred term.

A descriptive summary of all reported values and changes from baseline will be summarized by laboratory test category, treatment group, and visit.

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

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

All PK parameters will be described by standard summary statistics (N, mean and standard deviation).

All power measures will be described using standard summary statistics. Continuous variables will be summarized in terms of N, mean and standard deviation, and categorical variables will be summarized in terms of number and percentage of individuals in each category. Time-to-event data will be summarized using the Kaplan Meier method.

The incidence of ADA will be described by standard summary statistics (N, mean and standard deviation).

All PD parameters will be described by standard summary statistics (N, mean and standard deviation).

No interim analysis is planned for this study.

Table 6 below provides the sequences referred to in this application. Example 2 - Results of a Multicenter, Open Label, Dose Escalation Phase 1b Study of Antibody A in Individuals with Relapsed / Refractory Multiple Myeloma

Certain results of studies conducted according to the method as described in Example 1 are presented in Example 2 herein.

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

The pharmacokinetics of Antibody A were predictable and linear in the first two groups. Figure 1 shows the concentration of antibody A in the serum of each patient in the first two groups over time, measured in µg/mL, during cycle 1 and during part of cycle 2.

The pharmacodynamics of Antibody A showed a significant reduction in IL-18 levels in serum. Figure 2 shows the concentration of IL-18 in the serum of each patient in the first two groups over time, measured in pg/mL, during cycle 1 and during a portion of cycle 2. Figure 3 shows the concentration of IL-18bp in serum per patient of the first two groups over time, measured in pg/mL, during cycle 1 and during a portion of cycle 2. The concentration of free IL-18 in the patient's serum can be calculated from the IL-18 and IL-18bp concentration data based on formulas known in the art.

The third group is currently treated according to Example 1: 14 mg/kg group.

Table 6 - Sequence Listing SEQ ID NO describe sequence listing 1 Antibody 1 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 2 Antibody 1 HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 3 Antibody 1 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 4 Antibody 1 HCDR3 Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val 5 Antibody 1 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 6 Antibody 1 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 7 Antibody 1 LCDR2 Lys Ala Ser Thr Leu Glu Ser 8 Antibody 1 LCDR3 Gln Gln Ser Tyr Ser Thr Pro Trp Thr 9 Antibody 1_GL VH Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 10 Antibody 1_GL HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 11 Antibody 1_GL HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 12 Antibody 1_GL HCDR3 Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val 13 Antibody 1_GL VL Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 14 Antibody 1_GL LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 15 Antibody 1_GL LCDR2 Lys Ala Ser Thr Leu Glu Ser 16 Antibody 1_GL LCDR3 Gln Gln Ser Tyr Ser Thr Pro Trp Thr 17 Antibody 2 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 18 Antibody 2 HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 19 Antibody 2 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 20 Antibody 2 HCDR3 Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val twenty one Antibody 2 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asp Ile Ser Phe Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys twenty two Antibody 2 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala twenty three Antibody 2 LCDR2 Lys Ala Ser Thr Leu Glu Ser twenty four Antibody 2 LCDR3 Gln Asp Ile Ser Phe Pro Pro Trp Thr 25 Antibody 3 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 26 Antibody 3 HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 27 Antibody 3 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 28 Antibody 3 HCDR3 Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val 29 Antibody 3 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Tyr Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 30 Antibody 3 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 31 Antibody 3 LCDR2 Lys Ala Ser Thr Leu Glu Ser 32 Antibody 3 LCDR3 Gln Gln Ser Leu Tyr Pro Pro Trp Thr 33 Antibody 4 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 34 Antibody 4 HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 35 Antibody 4 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 36 Antibody 4 HCDR3 Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val 37 Antibody 4 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Asn Trp Asp Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 38 Antibody 4 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 39 Antibody 4 LCDR2 Lys Ala Ser Thr Leu Glu Ser 40 Antibody 4 LCDR3 Gln Gln Ser His His Pro Asn Trp Asp 41 Antibody 5 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 42 Antibody 5 HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 43 Antibody 5 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 44 Antibody 5 HCDR3 Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val 45 Antibody 5 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Ile Pro Gln Trp Asp Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 46 Antibody 5 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 47 Antibody 5 LCDR2 Lys Ala Ser Thr Leu Glu Ser 48 Antibody 5 LCDR3 Gln Gln Ser Leu Ile Pro Gln Trp Asp 49 Antibody 6 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 50 Antibody 6 HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 51 Antibody 6 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 52 Antibody 6 HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 53 Antibody 6 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Asn Ile Ala Phe Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 54 Antibody 6 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 55 Antibody 6 LCDR2 Lys Ala Ser Thr Leu Glu Ser 56 Antibody 6 LCDR3 Ala Asn Ile Ala Phe Pro Pro Trp Thr 57 Antibody 6_GL VH Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 58 Antibody 6_GL HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 59 Antibody 6_GL HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 60 Antibody 6_GL HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 61 Antibody 6_GL VL Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Ala Asn Ile Ala Phe Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 62 Antibody 6_GL LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 63 Antibody 6_GL LCDR2 Lys Ala Ser Thr Leu Glu Ser 64 Antibody 6_GL Ala Asn Ile Ala Phe Pro Pro Trp Thr 65 Antibody 7 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 66 Antibody 7 HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 67 Antibody 7 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 68 Antibody 7 HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 69 Antibody 7 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 70 Antibody 7 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 71 Antibody 7 LCDR2 Lys Ala Ser Thr Leu Glu Ser 72 Antibody 7 LCDR3 Gln Gln Ser His His Pro Pro Trp Thr 73 Antibody 7_GL VH Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 74 Antibody 7_GL HCDR1 Ser Gly Gly Tyr Tyr Trp Ser 75 Antibody 7_GL HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 76 Antibody 7_GL HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 77 Antibody 7_GL VL Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 78 Antibody 7_GL LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 79 Antibody 7_GL LCDR2 Lys Ala Ser Thr Leu Glu Ser 80 Antibody 7_GL LCDR3 Gln Gln Ser His His Pro Pro Trp Thr 81 Antibody 8_GL VH Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Gly Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Gly Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 82 Antibody 8_GL HCDR1 Ala Gly Gly Tyr Tyr Trp Ser 83 Antibody 8_GL HCDR2 Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Gly 84 Antibody 8_GL HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 85 Antibody 8_GL VL Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 86 Antibody 8_GL LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 87 Antibody 8_GL LCDR2 Lys Ala Ser Thr Leu Glu Ser 88 Antibody 8_GL LCDR3 Gln Gln Ser His His Pro Pro Trp Thr 89 Antibody 9 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Glu Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 90 Antibody 9 HCDR1 Ser Asp Gly Tyr Tyr Trp Ser 91 Antibody 9 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 92 Antibody 9 HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 93 Antibody 9 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 94 Antibody 9 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 95 Antibody 9 LCDR2 Lys Ala Ser Thr Leu Glu Ser 96 Antibody 9 LCDR3 Gln Gln Ser His His Pro Pro Trp Thr 97 Antibody 10 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Glu Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 98 Antibody 10 HCDR1 Ser Asp Gly Tyr Tyr Trp Ser 99 Antibody 10 HCDR2 Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Ser 100 Antibody 10 HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 101 Antibody 10 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gly Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp Thr Phe Ser Gln Gly Thr Lys Leu Glu Ile Lys 102 Antibody 10 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 103 Antibody 10 LCDR2 Lys Ala Ser Thr Leu Glu Ser 104 Antibody 10 LCDR3 Gln Gln Ser His His Pro Pro Trp Thr 105 Antibody 11 VH Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Glu Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Gly Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 106 Antibody 11 HCDR1 Ala Asp Gly Tyr Tyr Trp Ser 107 Antibody 11 HCDR2 Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Gly 108 Antibody 11 HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 109 Antibody 11 VL Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gly Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp Thr Phe Ser Gln Gly Thr Lys Leu Glu Ile Lys 110 Antibody 11 LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 111 Antibody 11 LCDR2 Lys Ala Ser Thr Leu Glu Ser 112 Antibody 11 LCDR3 Gln Gln Ser His His Pro Pro Trp Thr 113 Antibody 11_GL VH Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Gly Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 114 Antibody 11_GL HCDR1 Ala Asp Gly Tyr Tyr Trp Ser 115 Antibody 11_GL HCDR2 Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Gly 116 Antibody 11_GL HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 117 Antibody 11_GL VL Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 118 Antibody 11_GL LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 119 Antibody 11_GL LCDR2 Lys Ala Ser Thr Leu Glu Ser 120 Antibody 11_GL LCDR3 Gln Gln Ser His His Pro Pro Trp Thr 121 Antibody 12_GL (Antibody A) VH Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile Gly Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Gly Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 122 Antibody 12_GL (Antibody A) HCDR1 Ala Asp Gly Tyr Tyr Trp Ser 123 Antibody 12_GL (Antibody A) HCDR2 Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Gly 124 Antibody 12_GL (Antibody A) HCDR3 Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val 125 Antibody 12_GL (Antibody A) VL Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 126 Antibody 12_GL (Antibody A) LCDR1 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 127 Antibody 12_GL (Antibody A) LCDR2 Lys Ala Ser Thr Leu Glu Ser 128 Antibody 12_GL (Antibody A) LCDR3 Gln Gln Ser His His Pro Pro Trp Thr 129 HCDR1 Gly Tyr Tyr Phe His 130 HCDR2 Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys Asp 131 HCDR3 Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp Ala 132 LCDR1 Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr 133 LCDR2 Gly Ala Asn Lys Leu Gln Asp 134 LCDR3 Leu Gln Gly Ser Lys Phe Pro Leu Thr 135 hIL-18 Met Ala Ala Glu Pro Val Glu Asp Asn Cys Ile Asn Phe Val Ala Met Lys Phe Ile Asp Asn Thr Leu Tyr Phe Ile Ala Glu Asp Asp Glu Asn Leu Glu Ser Asp Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Asp Asn Ile Lys Asp Thr Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 136 Human Il-18 (PN) atggctgctg aaccagtaga agacaattgc atcaactttg tggcaatgaa atttattgac 60 aatacgcttt actttatagc tgaagatgat gaaaacctgg aatcagatta ctttggcaag 120 cttgaatcta aattatcagt cataagaaat ttgaatgacc aagttctctt cattgacca a 180 ggaaatcggc ctctatttga agatatgact gattctgact gtagagataa tgcaccccgg 240 accatattta ttataagtat gtataaagat agccagccta gaggtatggc tgtaactatc 300 tctgtgaagt gtgagaaaat ttcaactctc tcctgtgaga acaaaattat ttcctt taag 360 gaaatgaatc ctcctgataa catcaaggat acaaaaagtg acatcatatt ctttcagaga 420 agtgtcccag gacatgataa taagatgcaa tttgaatctt catcatacga aggatacttt 480 ctagcttgtg aaaaagagag agaccttttt aaactcattt tgaaaaaaga ggatgaattg 540 ggggatagat ctataatgtt cactgttcaa aacgaagact ag 582 137 H1 heavy chain Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr Tyr Phe His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys Asp Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 138 H1 heavy chain (PN) aggtgcagc tggtgcagag cggagccgag gtgaagaagc ctggcgccag cgtcaaggtg 60 tcctgtaagg tgtccggcga gatcagcacc ggctactact tccactgggt gaggcaggcc 120 cctggcaagg gcctggagtg gatgggcaga atcgaccccg aggacgacag caccaag tac 180 gccgagcggt tcaaggacag ggtgaccatg accgaggaca ccagcaccga taccgcctac 240 atggagctgt ccagcctgag aagcgaggat accgccgtgt actactgtac cacctggcgg 300 atctacagag acagcagcgg cagacccttc tacgtgatgg atg cctgggg ccagggcaca 360 ctagtgaccg tgtccagcgc cagcaccaag ggccccagcg tgttccccct ggcccccagc 420 agcaagagca ccagcggcgg cacagccgcc ctgggctgcc tggtgaagga ctacttcccc 480 gaaccggtga ccgtgtcctg gaacagcgga gccctgacca gcggcgtgca caccttcccc 540 gccgtgctgc agagcagcgg cctgtacagc ctgagcagcg tggtgaccgt gcc cagcagc 600 agcctgggca cccagaccta catctgtaac gtgaaccaca agcccagcaa caccaaggtg 660 gacaagaagg tggagcccaa gagctgtgac aagacccaca cctgcccccc ctgccctgcc 720 cccgagctgc tgggaggccc cagcgtgttc ctgttcc ccc ccaagcctaa ggacaccctg 780 atgatcagca gaacccccga ggtgacctgt gtggtggtgg atgtgagcca cgaggaccct 840 gaggtgaagt tcaactggta cgtggacggc gtggaggtgc acaatgccaa gaccaagccc 900 agggaggagc agtacaacag cacctaccgg gtggtgtccg tgctgaccgt gctgcaccag 960 gattggctga acggcaagga gtacaagtgt aaggtgtcca acaaggccct gcctgcccct 1020 at cgagaaaa ccatcagcaa ggccaagggc cagcccagag agccccaggt gtacaccctg 1080 ccccctagca gagatgagct gaccaagaac caggtgtccc tgacctgcct ggtgaagggc 1140 ttctacccca gcgacatcgc cgtggagtgg gagagcaacg gccagcccga gaac aactac 1200 aagaccaccc cccctgtgct ggacagcgat ggcagcttct tcctgtacag caagctgacc 1260 gtggacaaga gcagatggca gcagggcaac gtgttcagct gctccgtgat gcacgaggcc 1320 ctgcacaatc actacaccca gaagagcctg agcctgtccc ctggcaagtg a 1371 139 H1 variable region Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr Tyr Phe His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys Asp Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 140 H1 variable region (PN) caggtgcagc tggtgcagag cggagccgag gtgaagaagc ctggcgccag cgtcaaggtg 60 tcctgtaagg tgtccggcga gatcagcacc ggctactact tccactgggt gaggcaggcc 120 cctggcaagg gcctggagtg gatgggcaga atcgaccccg aggacgacag cacca agtac 180 gccgagcggt tcaaggacag ggtgaccatg accgaggaca ccagcaccga taccgcctac 240 atggagctgt ccagcctgag aagcgaggat accgccgtgt actactgtac cacctggcgg 300 atctacagag acagcagcgg cagacccttc tacgtgatgg at gcctgggg ccagggcaca 360 ctagtgaccg tgtccagc 378 141 L2 light chain Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 142 L2 light chain (PN) gatatccaga tgacccagtc ccccagcagc gtgtccgcct ctgtgggcga tagagtgacc 60 atcacctgcc tggccagcga ggacatctac acctacctga cctggtatca gcagaagcct 120 ggcaaggccc ctaagctgct gatctacggc gccaacaagc tgcaggacgg cgtgcc cagc 180 agattcagcg gcagcggctc cggcaccgac tacaccctga ccatcagcag cctgcagcct 240 gaggatttcg ccacctacta ctgcctgcag ggcagcaagt tccccctgac cttcggccag 300 ggcaccaagc tggagatcaa gcgtacggtg gccgccccca g cgtgttcat cttccccccc 360 agcgatgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaatgccc tgcagagcgg caacagccag 480 gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gtgaggtgac ccaccagggc 600 ctgtccagcc ccgtgaccaa gagcttcaac cggggcgagt gc 642 143 L2 variable region Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 144 L2 variable region (PN) gatatccaga tgacccagtc ccccagcagc gtgtccgcct ctgtgggcga tagagtgacc 60 atcacctgcc tggccagcga ggacatctac acctacctga cctggtatca gcagaagcct 120 ggcaaggccc ctaagctgct gatctacggc gccaacaagc tgcaggacgg cgtgcc cagc 180 agattcagcg gcagcggctc cggcaccgac tacaccctga ccatcagcag cctgcagcct 240 gaggatttcg ccacctacta ctgcctgcag ggcagcaagt tccccctgac cttcggccag 300 ggcaccaagc tggagatcaa g 321 145 H2 heavy chain Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr Tyr Phe His Trp Val Arg Arg Arg Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys Asp Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 146 H2 heavy chain (PN) caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg tttccggaga aataagtact ggatactatt tccactgggt gcgacgaagg 120 cctggaaaag ggcttgagtg gatgggaagg attgatcctg aggatgatag tact aaatat 180 gctgagaggt tcaaagacag agtcaccatg accgaggaca catctacaga cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtac cacatggcgg 300 atataccgag atagttctgg ccgcccccttc tatgttatgg atg cctgggg ccaagggaca 360 ctagtcacag tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 420 tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 480 gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540 gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600 agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 660 gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 720 cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaac ccaa ggacacccctc 780 atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 840 gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 900 cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 960 gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1020 atc gagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1080 cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1140 ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaaca actac 1200 aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1260 gtggacaaga gcaggtggca gcagggggaac gtcttctcat gctccgtgat gcatgaggct 1320 ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1368 147 H2 variable region Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr Tyr Phe His Trp Val Arg Arg Arg Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys Asp Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 148 H2 variable region (PN) caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg tttccggaga aataagtact ggatactatt tccactgggt gcgacgaagg 120 cctggaaaag ggcttgagtg gatgggaagg attgatcctg aggatgatag tact aaatat 180 gctgagaggt tcaaagacag agtcaccatg accgaggaca catctacaga cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtac cacatggcgg 300 atataccgag atagttctgg ccgcccccttc tatgttatgg atg cctgggg ccaagggaca 360 ctagtcacag tctcctca 378 149 H3 heavy chain Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr Tyr Phe His Phe Val Arg Arg Arg Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys Asp Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 150 H3 heavy chain (PN) caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg tttccggaga aataagtact ggatactatt tccactttgt gcgacgaagg 120 cctggaaaag ggcttgagtg gatgggaagg attgatcctg aggatgatag t actaaatat 180 gctgagaggt tcaaagacag agtcaccatg accgcagaca catctacaga cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccactt atttttgtac cacatggcgg 300 atataccgag atagttctgg ccgcccccttc tatgttatgg at gcctgggg ccaagggaca 360 ctagtcacag tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 420 tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 480 gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540 gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600 agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 660 gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 720 cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaac ccaa ggacacccctc 780 atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 840 gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 900 cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 960 gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1020 atc gagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1080 cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1140 ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaaca actac 1200 aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1260 gtggacaaga gcaggtggca gcagggggaac gtcttctcat gctccgtgat gcatgaggct 1320 ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1368 151 H3 variable region Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr Tyr Phe His Phe Val Arg Arg Arg Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys Asp Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 152 H3 variable region (PN) caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg tttccggaga aataagtact ggatactatt tccactttgt gcgacgaagg 120 cctggaaaag ggcttgagtg gatgggaagg attgatcctg aggatgatag t actaaatat 180 gctgagaggt tcaaagacag agtcaccatg accgcagaca catctacaga cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccactt atttttgtac cacatggcgg 300 atataccgag atagttctgg ccgcccccttc tatgttatgg at gcctgggg ccaagggaca 360 ctagtcacag tctcctca 378 153 L1 light chain Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 154 L1 light chain (PN) gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 1 80 aggttcagcg gcagtggatc tgggacagat ttcactctca ctatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtctacag ggttccaagt ttccgctcac gtttggccag 300 gggaccaagc tggagatcaa acgtacggtg gctgcaccat ctgt cttcat cttcccgcca 360 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420 cccagagagg ccaaagtaca gtggaaggtg gacaacgccc tccaatcggg taactcccag 480 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642 155 L1 variable region Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 156 L1 variable region (PN) gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 1 80 aggttcagcg gcagtggatc tgggacagat ttcactctca ctatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtctacag ggttccaagt ttccgctcac gtttggccag 300 gggaccaagc tggagatcaa a 321 157 L3 light chain Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Ile Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Glu Gly Asp Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 158 L3 light chain (PN) gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120 gggaaagccc ctcaactcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 1 80 aggttcagcg gcagtggatc tgggacagat tatactctca ctatcagcag cctgcagcct 240 gaagatgaag gggattacta ttgtctacag ggttccaagt ttccgctcac gtttggccag 300 gggaccaagc tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420 cccagagagg ccaaagtaca gtggaaggtg gacaacgccc tccaatcggg taactcccag 480 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645 159 L3 variable region Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Ile Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Glu Gly Asp Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 160 L3 variable region (PN) gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120 gggaaagccc ctcaactcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 1 80 aggttcagcg gcagtggatc tgggacagat tatactctca ctatcagcag cctgcagcct 240 gaagatgaag gggattacta ttgtctacag ggttccaagt ttccgctcac gtttggccag 300 gggaccaagc tggagatcaa a 321 161 2c10 rat-human IgG1 chimera Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr Tyr Phe His Phe Val Arg Arg Arg Pro Gly Gly Gly Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys Asp Arg Ala Thr Leu Thr Ala Gln Thr Ser Ser Asn Thr Ala Tyr Leu Asn Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 162 2c10 Rat-Human IgG1 Chimera (PN) gaggtccagc tacagcagtc tggggctgag cttgtgagac ctgggacctc tgtgaagtta 60 tcttgcaaag tttctggcga aataagtaca ggatactatt tccactttgt gaggcgaagg 120 cctggacagg gtctggaatg gataggaagg attgatcctg aggatgatag tacta aatat 180 gctgagaggt tcaaagacag ggcgacgctc actgcacaaa catcctccaa cacagcctac 240 ctgaacctca gcagcctgac ctctgaggac actgcaactt atttttgtac cacatggcgg 300 atataccgag atagttctgg ccgcccccttc tatgttatgg atgcctgggg tcaaggaaca 360 ctagtcacag tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 420 tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 480 gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540 gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600 agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 660 gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 720 cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaac ccaa ggacacccctc 780 atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 840 gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 900 cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 960 gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1020 atc gagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1080 cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1140 ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaaca actac 1200 aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1260 gtggacaaga gcaggtggca gcagggggaac gtcttctcat gctccgtgat gcatgaggct 1320 ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1368 163 2c10 rat-human CK chimera Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly Glu Thr Val Ser Ile Glu Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Gly Ile Gln Pro Glu Asp Glu Gly Asp Tyr Phe Cys Leu Gln Gly Ser Lys Phe Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 164 2c10 rat-human CK chimera (PN) gacattcaaa tgacccagtc tccagcttcc ctgtctgcat ctctgggaga aactgtctcc 60 atcgaatgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120 gggaaatctc ctcaactcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 18 0 cggttcagtg gcagtggatc tggcacacag tattctctca agatcagcgg catacaacct 240 gaagatgaag gggattattt ctgtctacag ggttccaagt ttccgctcac gttcggttct 300 gggaccaagc tggagatcaa acgtacggtg gctgcaccat ctgtcttcat ct tcccgcca 360 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420 cccagagagg ccaaagtaca gtggaaggtg gacaacgccc tccaatcggg taactcccag 480 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642 165 heavy chain acceptor framework Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr 166 light chain acceptor framework Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro 167 JH6 amino acid sequence added to SEQ ID NO: 37 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 168 Amino acid sequence of Jκ2 added to SEQ ID NO: 38 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

Figure 1. Serum concentrations of antibody A in human subjects with R/R MM in groups 1 and 2. The Y axis is the concentration of Antibody A in µg/mL. Each line refers to data from one patient. Each patient is also assigned a number. Patients 005-0001 and 005-0003 were administered in cycle 1 (day 1) and cycle 2 (day 1). The total amount of each dose given to the patient based on the patient's weight is shown in parentheses after each patient's number.

Figure 2. Serum concentrations of IL-18 in human subjects with R/R MM treated with Antibody A. 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 administered in cycle 1 (day 1) and cycle 2 (day 1) (day 29). "LLOQ" means lower limit of quantitation. The LLOQ was 79 pg/mL for patient 005-0001 and 54 pg/mL for all other patients. Samples < LLOQ are reported as LLOQ (LLOQ indicated by dotted line). The total amount of each dose given to the patient based on the patient's weight is shown in parentheses after each patient's number.

Figure 3. Serum concentrations of IL-18 binding protein in human subjects with R/R MM treated with Antibody A. 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 administered in cycle 1 (day 1) and cycle 2 (day 1) (day 29). The total amount of each dose given to the patient based on the patient's weight is shown in parentheses after each patient's number.

         
           <![CDATA[ <110> AVALO THERAPEUTICS, INC.]]>
           <![CDATA[ <120> Methods and treatments involving IL-18 antibody]]>
           <![CDATA[ <130> 01118-0050-00PCT]]>
           <![CDATA[ <160> 168 ]]>
           <![CDATA[ <170> PatentIn version 3.5]]>
           <![CDATA[ <210> 1]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1 VH]]>
           <![CDATA[ <400> 1]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 2]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1 HCDR1]]>
           <![CDATA[ <400> 2]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 3]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1 HCDR2]]>
           <![CDATA[ <400> 3]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 4]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1 HCDR3]]>
           <![CDATA[ <400> 4]]>
          Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 5]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1 VL]]>
           <![CDATA[ <400> 5]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 6]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1 LCDR1]]>
           <![CDATA[ <400> 6]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 7]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1 LCDR2]]>
           <![CDATA[ <400> 7]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 8]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1 LCDR3]]>
           <![CDATA[ <400> 8]]>
          Gln Gln Ser Tyr Ser Thr Pro Trp Thr
          1 5
           <![CDATA[ <210> 9]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1_GL VH]]>
           <![CDATA[ <400> 9]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 10]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1_GL HCDR1]]>
           <![CDATA[ <400> 10]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 11]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1_GL HCDR2]]>
           <![CDATA[ <400> 11]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 12]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1_GL HCDR3]]>
           <![CDATA[ <400> 12]]>
          Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 13]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1_GL VL]]>
           <![CDATA[ <400> 13]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 14]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1_GL LCDR1]]>
           <![CDATA[ <400> 14]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 15]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1_GL LCDR2]]>
           <![CDATA[ <400> 15]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 16]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 1_GL LCDR3]]>
           <![CDATA[ <400> 16]]>
          Gln Gln Ser Tyr Ser Thr Pro Trp Thr
          1 5
           <![CDATA[ <210> 17]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 2 VH]]>
           <![CDATA[ <400> 17]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 18]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 2 HCDR1]]>
           <![CDATA[ <400> 18]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 19]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 2 HCDR2]]>
           <![CDATA[ <400> 19]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 20]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 2 HCDR3]]>
           <![CDATA[ <400> 20]]>
          Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 21]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 2 VL]]>
           <![CDATA[ <400> 21]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asp Ile Ser Phe Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 22]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 2 LCDR1]]>
           <![CDATA[ <400> 22]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 23]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 2 LCDR2]]>
           <![CDATA[ <400> 23]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 24]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 2 LCDR3]]>
           <![CDATA[ <400> 24]]>
          Gln Asp Ile Ser Phe Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 25]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 3 VH]]>
           <![CDATA[ <400> 25]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 26]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 3 HCDR1]]>
           <![CDATA[ <400> 26]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 27]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 3 HCDR2]]>
           <![CDATA[ <400> 27]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 28]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 3 HCDR3]]>
           <![CDATA[ <400> 28]]>
          Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 29]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 3 VL]]>
           <![CDATA[ <400> 29]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Tyr Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 30]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 3 LCDR1]]>
           <![CDATA[ <400> 30]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 31]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 3 LCDR2]]>
           <![CDATA[ <400> 31]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 32]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 3 LCDR3]]>
           <![CDATA[ <400> 32]]>
          Gln Gln Ser Leu Tyr Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 33]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 4 VH]]>
           <![CDATA[ <400> 33]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 34]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 4 HCDR1]]>
           <![CDATA[ <400> 34]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 35]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 4 HCDR2]]>
           <![CDATA[ <400> 35]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 36]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 4 HCDR3]]>
           <![CDATA[ <400> 36]]>
          Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 37]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 4 VL]]>
           <![CDATA[ <400> 37]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Asn Trp
                          85 90 95
          Asp Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 38]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 4 LCDR1]]>
           <![CDATA[ <400> 38]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 39]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 4 LCDR2]]>
           <![CDATA[ <400> 39]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 40]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 4 LCDR3]]>
           <![CDATA[ <400> 40]]>
          Gln Gln Ser His His Pro Asn Trp Asp
          1 5
           <![CDATA[ <210> 41]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 5 VH]]>
           <![CDATA[ <400> 41]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 42]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 5 HCDR1]]>
           <![CDATA[ <400> 42]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 43]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 5 HCDR2]]>
           <![CDATA[ <400> 43]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 44]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 5 HCDR3]]>
           <![CDATA[ <400> 44]]>
          Thr Pro Ala Tyr Asp Gly Asp Ala Arg Ala Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 45]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 5 VL]]>
           <![CDATA[ <400> 45]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Ile Pro Gln Trp
                          85 90 95
          Asp Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 46]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 5 LCDR1]]>
           <![CDATA[ <400> 46]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 47]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 5 LCDR2]]>
           <![CDATA[ <400> 47]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 48]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 5 LCDR3]]>
           <![CDATA[ <400> 48]]>
          Gln Gln Ser Leu Ile Pro Gln Trp Asp
          1 5
           <![CDATA[ <210> 49]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6 VH]]>
           <![CDATA[ <400> 49]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 50]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6 HCDR1]]>
           <![CDATA[ <400> 50]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 51]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6 HCDR2]]>
           <![CDATA[ <400> 51]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 52]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6 HCDR3]]>
           <![CDATA[ <400> 52]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 53]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6 VL]]>
           <![CDATA[ <400> 53]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Asn Ile Ala Phe Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 54]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6 LCDR1]]>
           <![CDATA[ <400> 54]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 55]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6 LCDR2]]>
           <![CDATA[ <400> 55]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 56]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6 LCDR3]]>
           <![CDATA[ <400> 56]]>
          Ala Asn Ile Ala Phe Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 57]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6_GL VH]]>
           <![CDATA[ <400> 57]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 58]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6_GL HCDR1]]>
           <![CDATA[ <400> 58]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 59]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6_GL HCDR2]]>
           <![CDATA[ <400> 59]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 60]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6_GL HCDR3]]>
           <![CDATA[ <400> 60]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 61]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6_GL VL]]>
           <![CDATA[ <400> 61]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Asp Asp Phe Ala Thr Tyr Tyr Cys Ala Asn Ile Ala Phe Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 62]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6_GL LCDR1]]>
           <![CDATA[ <400> 62]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 63]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6_GL LCDR2]]>
           <![CDATA[ <400> 63]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 64]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 6_GL]]>
           <![CDATA[ <400> 64]]>
          Ala Asn Ile Ala Phe Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 65]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7 VH]]>
           <![CDATA[ <400> 65]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 66]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7 HCDR1]]>
           <![CDATA[ <400> 66]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 67]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7 HCDR2]]>
           <![CDATA[ <400> 67]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 68]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7 HCDR3]]>
           <![CDATA[ <400> 68]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 69]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7 VL]]>
           <![CDATA[ <400> 69]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 70]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7 LCDR1]]>
           <![CDATA[ <400> 70]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 71]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7 LCDR2]]>
           <![CDATA[ <400> 71]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 72]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7 LCDR3]]>
           <![CDATA[ <400> 72]]>
          Gln Gln Ser His His Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 73]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7_GL VH]]>
           <![CDATA[ <400> 73]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 74]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7_GL HCDR1]]>
           <![CDATA[ <400> 74]]>
          Ser Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 75]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7_GL HCDR2]]>
           <![CDATA[ <400> 75]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 76]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7_GL HCDR3]]>
           <![CDATA[ <400> 76]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 77]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7_GL VL]]>
           <![CDATA[ <400> 77]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 78]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7_GL LCDR1]]>
           <![CDATA[ <400> 78]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 79]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7_GL LCDR2]]>
           <![CDATA[ <400> 79]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 80]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 7_GL LCDR3]]>
           <![CDATA[ <400> 80]]>
          Gln Gln Ser His His Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 81]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 8_GL VH]]>
           <![CDATA[ <400> 81]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Gly
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Gly Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 82]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 8_GL HCDR1]]>
           <![CDATA[ <400> 82]]>
          Ala Gly Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 83]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 8_GL HCDR2]]>
           <![CDATA[ <400> 83]]>
          Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Gly
          1 5 10 15
           <![CDATA[ <210> 84]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 8_GL HCDR3]]>
           <![CDATA[ <400> 84]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 85]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 8_GL VL]]>
           <![CDATA[ <400> 85]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 86]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 8_GL LCDR1]]>
           <![CDATA[ <400> 86]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 87]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 8_GL LCDR2]]>
           <![CDATA[ <400> 87]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 88]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 8_GL LCDR3]]>
           <![CDATA[ <400> 88]]>
          Gln Gln Ser His His Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 89]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 9 VH]]>
           <![CDATA[ <400> 89]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Glu Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Asp
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 90]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 9 HCDR1]]>
           <![CDATA[ <400> 90]]>
          Ser Asp Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 91]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 9 HCDR2]]>
           <![CDATA[ <400> 91]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 92]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 9 HCDR3]]>
           <![CDATA[ <400> 92]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 93]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 9 VL]]>
           <![CDATA[ <400> 93]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 94]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 9 LCDR1]]>
           <![CDATA[ <400> 94]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 95]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 9 LCDR2]]>
           <![CDATA[ <400> 95]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 96]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 9 LCDR3]]>
           <![CDATA[ <400> 96]]>
          Gln Gln Ser His His Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 97]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 10 VH]]>
           <![CDATA[ <400> 97]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Glu Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser Asp
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Arg Ser Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 98]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 10 HCDR1]]>
           <![CDATA[ <400> 98]]>
          Ser Asp Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 99]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 10 HCDR2]]>
           <![CDATA[ <400> 99]]>
          Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Ser
          1 5 10 15
           <![CDATA[ <210> 100]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 10 HCDR3]]>
           <![CDATA[ <400> 100]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 101]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 10 VL]]>
           <![CDATA[ <400> 101]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gly Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp
                          85 90 95
          Thr Phe Ser Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 102]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 10 LCDR1]]>
           <![CDATA[ <400> 102]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 103]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 10 LCDR2]]>
           <![CDATA[ <400> 103]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 104]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 10 LCDR3]]>
           <![CDATA[ <400> 104]]>
          Gln Gln Ser His His Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 105]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11 VH]]>
           <![CDATA[ <400> 105]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Arg Leu Val Glu Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Asp
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Arg Gly Arg Val Thr Ile Ser Gly Asp Thr Pro Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 106]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11 HCDR1]]>
           <![CDATA[ <400> 106]]>
          Ala Asp Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 107]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11 HCDR2]]>
           <![CDATA[ <400> 107]]>
          Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Gly
          1 5 10 15
           <![CDATA[ <210> 108]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11 HCDR3]]>
           <![CDATA[ <400> 108]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 109]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11 VL]]>
           <![CDATA[ <400> 109]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gly Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp
                          85 90 95
          Thr Phe Ser Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 110]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11 LCDR1]]>
           <![CDATA[ <400> 110]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 111]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11 LCDR2]]>
           <![CDATA[ <400> 111]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 112]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11 LCDR3]]>
           <![CDATA[ <400> 112]]>
          Gln Gln Ser His His Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 113]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11_GL VH]]>
           <![CDATA[ <400> 113]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Asp
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Arg Gly Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 114]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11_GL HCDR1]]>
           <![CDATA[ <400> 114]]>
          Ala Asp Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 115]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11_GL HCDR2]]>
           <![CDATA[ <400> 115]]>
          Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Gly
          1 5 10 15
           <![CDATA[ <210> 116]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11_GL HCDR3]]>
           <![CDATA[ <400> 116]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 117]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11_GL VL]]>
           <![CDATA[ <400> 117]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 118]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11_GL LCDR1]]>
           <![CDATA[ <400> 118]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 119]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11_GL LCDR2]]>
           <![CDATA[ <400> 119]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 120]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 11_GL LCDR3]]>
           <![CDATA[ <400> 120]]>
          Gln Gln Ser His His Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 121]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 12_GL VH]]>
           <![CDATA[ <400> 121]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Asp
                      20 25 30
          Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
                  35 40 45
          Trp Ile Gly Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
              50 55 60
          Leu Lys Gly Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Asn Gln Phe
          65 70 75 80
          Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
                          85 90 95
          Cys Ala Arg Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe
                      100 105 110
          Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 122]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 12_GL HCDR1]]>
           <![CDATA[ <400> 122]]>
          Ala Asp Gly Tyr Tyr Trp Ser
          1 5
           <![CDATA[ <210> 123]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 12_GL HCDR2]]>
           <![CDATA[ <400> 123]]>
          Ser Leu Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Gly
          1 5 10 15
           <![CDATA[ <210> 124]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 12_GL HCDR3]]>
           <![CDATA[ <400> 124]]>
          Thr Pro Ala Tyr Phe Gly Gln Asp Arg Thr Asp Phe Phe Asp Val
          1 5 10 15
           <![CDATA[ <210> 125]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 12_GL VL]]>
           <![CDATA[ <400> 125]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
                  35 40 45
          Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser His His Pro Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 126]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 12_GL LCDR1]]>
           <![CDATA[ <400> 126]]>
          Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
          1 5 10
           <![CDATA[ <210> 127]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 12_GL LCDR2]]>
           <![CDATA[ <400> 127]]>
          Lys Ala Ser Thr Leu Glu Ser
          1 5
           <![CDATA[ <210> 128]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Antibody 12_GL LCDR3]]>
           <![CDATA[ <400> 128]]>
          Gln Gln Ser His His Pro Pro Trp Thr
          1 5
           <![CDATA[ <210> 129]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: HCDR1]]>
           <![CDATA[ <400> 129]]>
          Gly Tyr Tyr Phe His
          1 5
           <![CDATA[ <210> 130]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: HCDR2]]>
           <![CDATA[ <400> 130]]>
          Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe Lys
          1 5 10 15
          Asp
           <![CDATA[ <210> 131]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: HCDR3]]>
           <![CDATA[ <400> 131]]>
          Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val Met Asp
          1 5 10 15
          Ala
           <![CDATA[ <210> 132]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: LCDR1]]>
           <![CDATA[ <400> 132]]>
          Leu Ala Ser Glu Asp Ile Tyr Thr Tyr Leu Thr
          1 5 10
           <![CDATA[ <210> 133]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: LCDR2]]>
           <![CDATA[ <400> 133]]>
          Gly Ala Asn Lys Leu Gln Asp
          1 5
           <![CDATA[ <210> 134]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: LCDR3]]>
           <![CDATA[ <400> 134]]>
          Leu Gln Gly Ser Lys Phe Pro Leu Thr
          1 5
           <![CDATA[ <210> 135]]>
           <![CDATA[ <211> 193]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <223> Human IL-18]]>
           <![CDATA[ <400> 135]]>
          Met Ala Ala Glu Pro Val Glu Asp Asn Cys Ile Asn Phe Val Ala Met
          1 5 10 15
          Lys Phe Ile Asp Asn Thr Leu Tyr Phe Ile Ala Glu Asp Asp Glu Asn
                      20 25 30
          Leu Glu Ser Asp Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile
                  35 40 45
          Arg Asn Leu Asn Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro
              50 55 60
          Leu Phe Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg
          65 70 75 80
          Thr Ile Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met
                          85 90 95
          Ala Val Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys
                      100 105 110
          Glu Asn Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile
                  115 120 125
          Lys Asp Thr Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly
              130 135 140
          His Asp Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe
          145 150 155 160
          Leu Ala Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys
                          165 170 175
          Glu Asp Glu Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu
                      180 185 190
          Asp
           <![CDATA[ <210> 136]]>
           <![CDATA[ <211> 582]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Sapiens]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <221> misc_feature]]>
           <![CDATA[ <223> Human IL-18 (PN)]]>
           <![CDATA[ <400> 136]]>
          atggctgctg aaccagtaga agacaattgc atcaactttg tggcaatgaa atttattgac 60
          aatacgcttt actttatagc tgaagatgat gaaaacctgg aatcagatta ctttggcaag 120
          cttgaatcta aattatcagt cataagaaat ttgaatgacc aagttctctt cattgaccaa 180
          ggaaatcggc ctctatttga agatatgact gattctgact gtagagataa tgcaccccgg 240
          accatattta ttataagtat gtataaagat agccagccta gaggtatggc tgtaactatc 300
          tctgtgaagt gtgagaaaat ttcaactctc tcctgtgaga acaaaattat ttcctttaag 360
          gaaatgaatc ctcctgataa catcaaggat acaaaaagtg acatcatatt ctttcagaga 420
          agtgtccccag gacatgataa taagatgcaa tttgaatctt catcatacga aggatacttt 480
          ctagcttgtg aaaaagagag agaccttttt aaactcattt tgaaaaaaga ggatgaattg 540
          ggggatagat ctataatgtt cactgttcaa aacgaagact ag 582
           <![CDATA[ <210> 137]]>
           <![CDATA[ <211> 456]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H1 heavy chain]]>
           <![CDATA[ <400> 137]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr
                      20 25 30
          Tyr Phe His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val
                      100 105 110
          Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
                  115 120 125
          Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
              130 135 140
          Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
          145 150 155 160
          Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
                          165 170 175
          His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
                      180 185 190
          Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
                  195 200 205
          Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
              210 215 220
          Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
          225 230 235 240
          Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
                          245 250 255
          Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
                      260 265 270
          Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
                  275 280 285
          Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
              290 295 300
          Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
          305 310 315 320
          Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
                          325 330 335
          Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
                      340 345 350
          Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
                  355 360 365
          Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
              370 375 380
          Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
          385 390 395 400
          Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
                          405 410 415
          Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
                      420 425 430
          Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
                  435 440 445
          Ser Leu Ser Leu Ser Pro Gly Lys
              450 455
           <![CDATA[ <210> 138]]>
           <![CDATA[ <211> 1370]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H1 heavy chain (PN)]]>
           <![CDATA[ <400> 138]]>
          aggtgcagct ggtgcagagc ggagccgagg tgaagaagcc tggcgccagc gtcaaggtgt 60
          cctgtaaggt gtccggcgag atcagcaccg gctactactt ccactgggtg aggcaggccc 120
          ctggcaaggg cctggagtgg atgggcagaa tcgaccccga ggacgacagc accaagtacg 180
          ccgagcggtt caaggacagg gtgaccatga ccgaggacac cagcaccgat accgcctaca 240
          tggagctgtc cagcctgaga agcgaggata ccgccgtgta ctactgtacc acctggcgga 300
          tctacagaga cagcagcggc agacccttct acgtgatgga tgcctggggc cagggcacac 360
          tagtgaccgt gtccagcgcc agcaccaagg gccccagcgt gttccccctg gcccccagca 420
          gcaagagcac cagcggcggc acagccgccc tgggctgcct ggtgaaggac tacttccccg 480
          aaccggtgac cgtgtcctgg aacagcggag ccctgaccag cggcgtgcac accttccccg 540
          ccgtgctgca gagcagcggc ctgtacagcc tgagcagcgt ggtgaccgtg cccagcagca 600
          gcctgggcac ccagacctac atctgtaacg tgaaccacaa gcccagcaac accaaggtgg 660
          acaagaaggt ggagcccaag agctgtgaca agaccacac ctgccccccc tgccctgccc 720
          ccgagctgct gggaggcccc agcgtgttcc tgttcccccc caagcctaag gacaccctga 780
          tgatcagcag aacccccgag gtgacctgtg tggtggtgga tgtgagccac gaggacccctg 840
          aggtgaagtt caactggtac gtggacggcg tggaggtgca caatgccaag accaagccca 900
          gggaggagca gtacaacagc acctaccggg tggtgtccgt gctgaccgtg ctgcaccagg 960
          attggctgaa cggcaaggag tacaagtgta aggtgtccaa caaggccctg cctgccccta 1020
          tcgagaaaac catcagcaag gccaagggcc agcccagaga gccccaggtg tacaccctgc 1080
          cccctagcag agatgagctg accaagaacc aggtgtccct gacctgcctg gtgaagggct 1140
          tctaccccag cgacatcgcc gtggagtggg agagcaacgg ccagcccgag aacaactaca 1200
          agaccacccc ccctgtgctg gacagcgatg gcagcttctt cctgtacagc aagctgaccg 1260
          tggacaagag cagatggcag cagggcaacg tgttcagctg ctccgtgatg cacgaggccc 1320
          tgcacaatca ctacacccag aagagcctga gcctgtcccc tggcaagtga 1370
           <![CDATA[ <210> 139]]>
           <![CDATA[ <211> 126]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H1 variable region]]>
           <![CDATA[ <400> 139]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr
                      20 25 30
          Tyr Phe His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val
                      100 105 110
          Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 140]]>
           <![CDATA[ <211> 378]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H1 Variable Region (PN)]]>
           <![CDATA[ <400> 140]]>
          caggtgcagc tggtgcagag cggagccgag gtgaagaagc ctggcgccag cgtcaaggtg 60
          tcctgtaagg tgtccggcga gatcagcacc ggctactact tccactgggt gaggcaggcc 120
          cctggcaagg gcctggagtg gatggggcaga atcgaccccg aggacgacag caccaagtac 180
          gccgagcggt tcaaggacag ggtgaccatg accgaggaca ccagcaccga taccgcctac 240
          atggagctgt ccagcctgag aagcgaggat accgccgtgt actactgtac cacctggcgg 300
          atctacagag acagcagcgg cagacccttc tacgtgatgg atgcctgggg ccagggcaca 360
          ctagtgaccg tgtccagc 378
           <![CDATA[ <210> 141]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L2 light chain]]>
           <![CDATA[ <400> 141]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr
                      20 25 30
          Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 142]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L2 light chain (PN)]]>
           <![CDATA[ <400> 142]]>
          gatatccaga tgacccagtc ccccagcagc gtgtccgcct ctgtgggcga tagagtgacc 60
          atcacctgcc tggccagcga ggacatctac acctacctga cctggtatca gcagaagcct 120
          ggcaaggccc ctaagctgct gatctacggc gccaacaagc tgcaggacgg cgtgcccagc 180
          agattcagcg gcagcggctc cggcaccgac tacaccctga ccatcagcag cctgcagcct 240
          gaggatttcg ccacctacta ctgcctgcag ggcagcaagt tccccctgac cttcggccag 300
          ggcaccaagc tggagatcaa gcgtacggtg gccgccccca gcgtgttcat cttccccccc 360
          agcgatgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac 420
          ccccgggagg ccaaggtgca gtggaaggtg gacaatgccc tgcagagcgg caacagccag 480
          gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540
          ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gtgaggtgac ccaccagggc 600
          ctgtccagcc ccgtgaccaa gagcttcaac cggggcgagt gc 642
           <![CDATA[ <210> 143]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L2 variable region]]>
           <![CDATA[ <400> 143]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr
                      20 25 30
          Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 144]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L2 Variable Region (PN)]]>
           <![CDATA[ <400> 144]]>
          gatatccaga tgacccagtc ccccagcagc gtgtccgcct ctgtgggcga tagagtgacc 60
          atcacctgcc tggccagcga ggacatctac acctacctga cctggtatca gcagaagcct 120
          ggcaaggccc ctaagctgct gatctacggc gccaacaagc tgcaggacgg cgtgcccagc 180
          agattcagcg gcagcggctc cggcaccgac tacaccctga ccatcagcag cctgcagcct 240
          gaggatttcg ccacctacta ctgcctgcag ggcagcaagt tccccctgac cttcggccag 300
          ggcaccaagc tggagatcaa g 321
           <![CDATA[ <210> 145]]>
           <![CDATA[ <211> 456]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H2 heavy chain]]>
           <![CDATA[ <400> 145]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr
                      20 25 30
          Tyr Phe His Trp Val Arg Arg Arg Pro Gly Lys Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val
                      100 105 110
          Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
                  115 120 125
          Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
              130 135 140
          Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
          145 150 155 160
          Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
                          165 170 175
          His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
                      180 185 190
          Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
                  195 200 205
          Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
              210 215 220
          Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
          225 230 235 240
          Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
                          245 250 255
          Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
                      260 265 270
          Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
                  275 280 285
          Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
              290 295 300
          Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
          305 310 315 320
          Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
                          325 330 335
          Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
                      340 345 350
          Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
                  355 360 365
          Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
              370 375 380
          Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
          385 390 395 400
          Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
                          405 410 415
          Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
                      420 425 430
          Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
                  435 440 445
          Ser Leu Ser Leu Ser Pro Gly Lys
              450 455
           <![CDATA[ <210> 146]]>
           <![CDATA[ <211> 1368]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H2 heavy chain (PN)]]>
           <![CDATA[ <400> 146]]>
          caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
          tcctgcaagg tttccggaga aataagtact ggatactatt tccactgggt gcgacgaagg 120
          cctggaaaag ggcttgagtg gatgggaagg attgatcctg aggatgatag tactaaatat 180
          gctgagaggt tcaaagacag agtcaccatg accgaggaca catctacaga cacagcctac 240
          atggagctga gcagcctgag atctgaggac acggccgtgt attackgtac cacatggcgg 300
          atataccgag atagttctgg ccgccccttc tatgttatgg atgcctgggg ccaagggaca 360
          ctagtcacag tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 420
          tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 480
          gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540
          gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600
          agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 660
          gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 720
          cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 780
          atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 840
          gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 900
          cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 960
          gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1020
          atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1080
          cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1140
          ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1200
          aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1260
          gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1320
          ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1368
           <![CDATA[ <210> 147]]>
           <![CDATA[ <211> 126]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H2 variable region]]>
           <![CDATA[ <400> 147]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr
                      20 25 30
          Tyr Phe His Trp Val Arg Arg Arg Pro Gly Lys Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val
                      100 105 110
          Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 148]]>
           <![CDATA[ <211> 378]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H2 Variable Region (PN)]]>
           <![CDATA[ <400> 148]]>
          caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
          tcctgcaagg tttccggaga aataagtact ggatactatt tccactgggt gcgacgaagg 120
          cctggaaaag ggcttgagtg gatgggaagg attgatcctg aggatgatag tactaaatat 180
          gctgagaggt tcaaagacag agtcaccatg accgaggaca catctacaga cacagcctac 240
          atggagctga gcagcctgag atctgaggac acggccgtgt attackgtac cacatggcgg 300
          atataccgag atagttctgg ccgccccttc tatgttatgg atgcctgggg ccaagggaca 360
          ctagtcacag tctcctca 378
           <![CDATA[ <210> 149]]>
           <![CDATA[ <211> 456]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H3 heavy chain]]>
           <![CDATA[ <400> 149]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr
                      20 25 30
          Tyr Phe His Phe Val Arg Arg Arg Pro Gly Lys Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys
                          85 90 95
          Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val
                      100 105 110
          Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
                  115 120 125
          Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
              130 135 140
          Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
          145 150 155 160
          Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
                          165 170 175
          His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
                      180 185 190
          Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
                  195 200 205
          Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
              210 215 220
          Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
          225 230 235 240
          Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
                          245 250 255
          Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
                      260 265 270
          Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
                  275 280 285
          Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
              290 295 300
          Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
          305 310 315 320
          Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
                          325 330 335
          Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
                      340 345 350
          Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
                  355 360 365
          Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
              370 375 380
          Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
          385 390 395 400
          Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
                          405 410 415
          Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
                      420 425 430
          Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
                  435 440 445
          Ser Leu Ser Leu Ser Pro Gly Lys
              450 455
           <![CDATA[ <210> 150]]>
           <![CDATA[ <211> 1368]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H3 heavy chain (PN)]]>
           <![CDATA[ <400> 150]]>
          caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
          tcctgcaagg tttccggaga aataagtact ggatactatt tccactttgt gcgacgaagg 120
          cctggaaaag ggcttgagtg gatgggaagg attgatcctg aggatgatag tactaaatat 180
          gctgagaggt tcaaagacag agtcaccatg accgcagaca catctacaga cacagcctac 240
          atggagctga gcagcctgag atctgaggac acggccactt atttttgtac cacatggcgg 300
          atataccgag atagttctgg ccgccccttc tatgttatgg atgcctgggg ccaagggaca 360
          ctagtcacag tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 420
          tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 480
          gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540
          gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600
          agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 660
          gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 720
          cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 780
          atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 840
          gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 900
          cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 960
          gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1020
          atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1080
          cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1140
          ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1200
          aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1260
          gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1320
          ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1368
           <![CDATA[ <210> 151]]>
           <![CDATA[ <211> 126]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H3 variable region]]>
           <![CDATA[ <400> 151]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr
                      20 25 30
          Tyr Phe His Phe Val Arg Arg Arg Pro Gly Lys Gly Leu Glu Trp Met
                  35 40 45
          Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe
              50 55 60
          Lys Asp Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys
                          85 90 95
          Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val
                      100 105 110
          Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 152]]>
           <![CDATA[ <211> 378]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: H3 Variable Region (PN)]]>
           <![CDATA[ <400> 152]]>
          caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
          tcctgcaagg tttccggaga aataagtact ggatactatt tccactttgt gcgacgaagg 120
          cctggaaaag ggcttgagtg gatgggaagg attgatcctg aggatgatag tactaaatat 180
          gctgagaggt tcaaagacag agtcaccatg accgcagaca catctacaga cacagcctac 240
          atggagctga gcagcctgag atctgaggac acggccactt atttttgtac cacatggcgg 300
          atataccgag atagttctgg ccgccccttc tatgttatgg atgcctgggg ccaagggaca 360
          ctagtcacag tctcctca 378
           <![CDATA[ <210> 153]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L1 light chain]]>
           <![CDATA[ <400> 153]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr
                      20 25 30
          Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 154]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L1 light chain (PN)]]>
           <![CDATA[ <400> 154]]>
          gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120
          gggaaagccc ctaagctcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat ttcactctca ctatcagcag cctgcagcct 240
          gaagattttg caacttacta ttgtctacag ggttccaagt ttccgctcac gtttggccag 300
          gggaccaagc tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
          tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
          cccagagagg ccaaagtaca gtggaaggtg gacaacgccc tccaatcggg taactcccag 480
          gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
          ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
          ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
           <![CDATA[ <210> 155]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L1 variable region]]>
           <![CDATA[ <400> 155]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr
                      20 25 30
          Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 156]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L1 Variable Region (PN)]]>
           <![CDATA[ <400> 156]]>
          gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120
          gggaaagccc ctaagctcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat ttcactctca ctatcagcag cctgcagcct 240
          gaagattttg caacttacta ttgtctacag ggttccaagt ttccgctcac gtttggccag 300
          gggaccaagc tggagatcaa a 321
           <![CDATA[ <210> 157]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L3 light chain]]>
           <![CDATA[ <400> 157]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr
                      20 25 30
          Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Glu Gly Asp Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 158]]>
           <![CDATA[ <211> 645]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L3 light chain (PN)]]>
           <![CDATA[ <400> 158]]>
          gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120
          gggaaagccc ctcaactcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat tatactctca ctatcagcag cctgcagcct 240
          gaagatgaag gggattacta ttgtctacag ggttccaagt ttccgctcac gtttggccag 300
          gggaccaagc tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
          tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
          cccagagagg ccaaagtaca gtggaaggtg gacaacgccc tccaatcggg taactcccag 480
          gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
          ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
          ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
           <![CDATA[ <210> 159]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L3 variable region]]>
           <![CDATA[ <400> 159]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr
                      20 25 30
          Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Glu Gly Asp Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 160]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: L3 Variable Region (PN)]]>
           <![CDATA[ <400> 160]]>
          gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120
          gggaaagccc ctcaactcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat tatactctca ctatcagcag cctgcagcct 240
          gaagatgaag gggattacta ttgtctacag ggttccaagt ttccgctcac gtttggccag 300
          gggaccaagc tggagatcaa a 321
           <![CDATA[ <210> 161]]>
           <![CDATA[ <211> 456]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: 2c10 rat-human IgG1 chimera]]>
           <![CDATA[ <400> 161]]>
          Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
          1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Val Ser Gly Glu Ile Ser Thr Gly Tyr
                      20 25 30
          Tyr Phe His Phe Val Arg Arg Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Arg Ile Asp Pro Glu Asp Asp Ser Thr Lys Tyr Ala Glu Arg Phe
              50 55 60
          Lys Asp Arg Ala Thr Leu Thr Ala Gln Thr Ser Ser Asn Thr Ala Tyr
          65 70 75 80
          Leu Asn Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys
                          85 90 95
          Thr Thr Trp Arg Ile Tyr Arg Asp Ser Ser Gly Arg Pro Phe Tyr Val
                      100 105 110
          Met Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
                  115 120 125
          Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
              130 135 140
          Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
          145 150 155 160
          Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
                          165 170 175
          His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
                      180 185 190
          Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
                  195 200 205
          Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
              210 215 220
          Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
          225 230 235 240
          Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
                          245 250 255
          Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
                      260 265 270
          Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
                  275 280 285
          Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
              290 295 300
          Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
          305 310 315 320
          Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
                          325 330 335
          Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
                      340 345 350
          Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
                  355 360 365
          Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
              370 375 380
          Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
          385 390 395 400
          Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
                          405 410 415
          Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
                      420 425 430
          Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
                  435 440 445
          Ser Leu Ser Leu Ser Pro Gly Lys
              450 455
           <![CDATA[ <210> 162]]>
           <![CDATA[ <211> 1368]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: 2c10 rat-human IgG1 chimera (PN)]]>
           <![CDATA[ <400> 162]]>
          gaggtccagc tacagcagtc tggggctgag cttgtgagac ctgggacctc tgtgaagtta 60
          tcttgcaaag tttctggcga aataagtaca ggatactatt tccactttgt gaggcgaagg 120
          cctggacagg gtctggaatg gataggagg attgatcctg aggatgatag tactaaatat 180
          gctgagaggt tcaaagacag ggcgacgctc actgcacaaa catcctccaa cacagcctac 240
          ctgaacctca gcagcctgac ctctgaggac actgcaactt atttttgtac cacatggcgg 300
          atataccgag atagttctgg ccgccccttc tatgttatgg atgcctgggg tcaaggaaca 360
          ctagtcacag tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 420
          tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 480
          gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540
          gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600
          agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 660
          gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 720
          cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 780
          atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 840
          gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 900
          cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 960
          gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1020
          atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1080
          cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1140
          ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1200
          aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1260
          gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1320
          ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1368
           <![CDATA[ <210> 163]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: 2c10 rat-human CK chimera]]>
           <![CDATA[ <400> 163]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly
          1 5 10 15
          Glu Thr Val Ser Ile Glu Cys Leu Ala Ser Glu Asp Ile Tyr Thr Tyr
                      20 25 30
          Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
                  35 40 45
          Tyr Gly Ala Asn Lys Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Gly Ile Gln Pro
          65 70 75 80
          Glu Asp Glu Gly Asp Tyr Phe Cys Leu Gln Gly Ser Lys Phe Pro Leu
                          85 90 95
          Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 164]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: 2c10 rat-human CK chimera (PN)]]>
           <![CDATA[ <400> 164]]>
          gacattcaaa tgacccagtc tccagcttcc ctgtctgcat ctctgggaga aactgtctcc 60
          atcgaatgtc tggcaagtga ggacatatac acttatttaa catggtatca gcagaaacca 120
          gggaaatctc ctcaactcct gatctatggt gcaaataagt tgcaagatgg ggtcccatca 180
          cggttcagtg gcagtggatc tggcacacag tattctctca agatcagcgg catacaacct 240
          gaagatgaag gggattattt ctgtctacag ggttccaagt ttccgctcac gttcggttct 300
          gggaccaagc tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
          tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
          cccagagagg ccaaagtaca gtggaaggtg gacaacgccc tccaatcggg taactcccag 480
          gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
          ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
          ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
           <![CDATA[ <210> 165]]>
           <![CDATA[ <211> 98]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: heavy chain acceptor framework]]>
           <![CDATA[ <400> 165]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
                      20 25 30
          Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
                  35 40 45
          Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Thr
           <![CDATA[ <210> 166]]>
           <![CDATA[ <211> 95]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Light Chain Acceptor Framework]]>
           <![CDATA[ <400> 166]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro
                          85 90 95
           <![CDATA[ <210> 167]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Added to the JH6 amino acid sequence of SEQ ID NO: 37]]>
           <![CDATA[ <400> 167]]>
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
          1 5 10
           <![CDATA[ <210> 168]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Synthesis: Jκ 2 amino acid sequence added to SEQ ID NO: 38]]>
           <![CDATA[ <400> 168]]>
          Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
          1 5 10
          
      

Claims (55)

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 The -18 antibody contains the following six CDRs: (a) HCDR1 having the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 having the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 having the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 having the amino acid sequence of SEQ ID NO: 126; (e) LCDR2 having the amino acid sequence of SEQ ID NO: 127; and (f) LCDR3 having the amino acid sequence of SEQ ID NO: 128; and i) where the individual has active multiple myeloma despite prior therapy with proteasome inhibitors, immunomodulators, and anti-CD38 antibodies; and/or ii) where the individual has measurable myeloma based on any of the following: a. Serum M-protein greater than 0.5 g/dL; b. Urinary 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 individual has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1; and/or iv) Where the individual has undergone a prior autologous hematopoietic stem cell transplant more than 100 days prior to the Screening Visit. The method according to claim 1, wherein the individual is not administered an immunomodulatory drug while administering the anti-IL-18 antibody. The method of claim 2, wherein the immunomodulatory drug is selected from systemic glucocorticoids, anti-TNFα antibodies, anti-IL-17 antibodies, anti-IL-12/23 antibodies, PDE-4 inhibitors, JAK inhibitors, IL -6 inhibitors, rituximab, methotrexate, cyclosporine, and mycophenolate. The method according to any one of claims 1 to 3, wherein the individual has elevated free or total serum or bone marrow IL-18 levels. The method according to any one of claims 1 to 4, wherein the serum or bone marrow IL-18 content is measured before administering the anti-IL-18 antibody. The method according to any one of claims 1 to 5, wherein the serum or bone marrow IL-18 content is measured after administration of the anti-IL-18 antibody, and used as a sign of therapeutic effectiveness as appropriate. The method according to any one of claims 1 to 6, wherein the level of IL-18 in the serum or bone marrow is increased compared to the level in an individual without active R/R multiple myeloma or compared to a negative control . The method according to any one of claims 1 to 7, wherein the serum or bone marrow IL-18 content is free IL-18, where the free IL-18 content is calculated as appropriate. The method according to any one of claims 1 to 7, wherein the serum or bone marrow IL-18 content is total IL-18. The method according to any one of claims 1 to 8, wherein the individual has elevated free IL-18. The method according to any one of claims 1 to 7 or 10, wherein the individual has elevated total IL-18. A method of treating active relapsed/refractory (R/R) multiple myeloma comprising administering an effective amount of an anti-IL-18 antibody to a human subject diagnosed with multiple myeloma, and wherein an untreated An individual with active R/R multiple myeloma has elevated free or total IL-18 levels in serum or bone marrow compared to an individual with active R/R multiple myeloma, wherein the anti-IL-18 antibody comprises the following six CDRs: (a) HCDR1 having the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 having the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 having the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 having the amino acid sequence of SEQ ID NO: 126; (e) LCDR2 having the amino acid sequence of SEQ ID NO: 127; and (f) LCDR3 having the amino acid sequence of SEQ ID NO: 128; and optionally a) where the individual has active multiple myeloma despite prior therapy with proteasome inhibitors, immunomodulators, and anti-CD38 antibodies; and/or b) where the individual has measurable myeloma based on any of the following: a. Serum M-protein greater than 0.5 g/dL; b. Urinary 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 individual has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1; and/or d) Where the individual has undergone a prior autologous hematopoietic stem cell transplant more than 100 days prior to the Screening Visit. The method according to claim 12, wherein the serum or bone marrow IL-18 level is measured before administering the anti-IL-18 antibody. The method according to claim 12 or 13, wherein the serum or bone marrow IL-18 content is measured after administration of the anti-IL-18 antibody, and used as a sign of therapeutic effectiveness as appropriate. The method of any one of claims 12 to 14, wherein serum free or total IL-18 levels are elevated compared to levels in individuals without active R/R multiple myeloma. The method according to any one of claims 12 to 14, wherein the serum or bone marrow IL-18 content is free IL-18, where the free IL-18 content is calculated as appropriate. The method according to any one of claims 12 to 14, wherein the serum or bone marrow IL-18 content is total IL-18. The method according to any one of claims 1 to 17, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence at least 90% identical to the entire sequence of SEQ ID NO: 121. The method according to any one of claims 1 to 18, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence consistent with the entire sequence of SEQ ID NO: 121. The method according to any one of claims 1 to 19, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence at least 90% identical to the entire sequence of SEQ ID NO: 125. The method according to any one of claims 1 to 20, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence consistent with the entire sequence of SEQ ID NO: 125. The method according to any one of claims 1 to 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 times the full sequence of SEQ ID NO: 121 % identical, and the antibody VL domain is at least 90% identical to the complete sequence of SEQ ID NO: 125. The method according to any one of claims 1 to 22, wherein the anti-IL-18 antibody is administered in the form of a pharmaceutically acceptable composition. The method of any one of claims 1 to 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 vote with. The method of any one of claims 1 to 24, comprising administering to the individual a dose of 10, 30, 100, 300 or 1000 mg of the anti-IL-18 antibody. The method according to any one of claims 1 to 24, comprising administering to the individual a dose of 10 to 30 mg/kg of the anti-IL-18 antibody. The method of any one of claims 1 to 26, comprising administering to the individual a dose of 0.03, 0.1 or 0.3 mg/kg of the anti-IL-18 antibody. The method according to any one of claims 1 to 27, comprising administering to the individual the anti-IL-18 antibody at a dose of 0.01 mg/kg to 36 mg/kg. The method according to any one of claims 1 to 28, comprising administering to the individual the anti-IL-18 antibody at a dose of 4 mg/kg, or 9 mg/kg or 14 mg/kg. The method of any one of claims 1 to 29, wherein the anti-IL-18 antibody is administered intravenously. The method of any one of claims 1 to 30, wherein the anti-IL-18 antibody is administered subcutaneously. The method of any one of claims 1 to 31, wherein the anti-IL-18 antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks . The method of any one of claims 1 to 32, wherein the anti-IL-18 antibody is administered on Day 1 of a 28-day treatment cycle. The method according to any one of claims 1 to 33, comprising a dose of 4 mg/kg on day 1 of a 28-day treatment cycle, a dose of 9 mg/kg on day 1 of a 28-day treatment cycle, or The subject is administered the anti-IL-18 antibody at a dose of 14 mg/kg on Day 1 of a 28-day treatment cycle. The method of any one of claims 1 to 34, wherein the individual is 18 years of age or older. The method of any one of claims 1 to 35, wherein treatment with the anti-IL-18 antibody shortens time to response (TTR) compared to standard of care therapy. The method of any one of claims 1 to 36, wherein treatment with the anti-IL-18 antibody prolongs progression-free survival (PFS) compared to standard-of-care therapy. The method of any one of claims 1 to 37, wherein treatment with the anti-IL-18 antibody prolongs the duration of response (DOR) compared to standard-of-care therapy. The method of any one of claims 1 to 38, wherein the individual achieves a strict complete response (sCR) according to the International Myeloma Working Group (IMWG) response guidelines after two or more 28-day treatment cycles . The method of any one of claims 1 to 39, wherein the individual achieves a complete response (CR) according to IMWG response criteria after two or more 28-day treatment cycles. The method of any one of claims 1 to 40, wherein the individual achieves a very good partial response (VGPR) according to IMWG response guidelines after two or more 28-day treatment cycles. The method of any one of claims 1 to 41, wherein the individual achieves a partial response (PR) according to IMWG response criteria after two or more 28-day treatment cycles. The method of any one of claims 1 to 42, wherein after administering the anti-IL-18 antibody one or more times, as measured by SPEP, the individual's serum M-protein is reduced by greater than or equal to 90% . The method of any one of claims 1 to 42, wherein after administering the anti-IL-18 antibody one or more times, as measured by SPEP, the individual's serum M-protein is reduced by greater than or equal to 50% . The method of any one of claims 1 to 42, wherein after administering the anti-IL-18 antibody one or more times, as measured by SPEP, the individual's serum M protein is reduced by greater than or equal to 25%, And wherein after one or more administrations of the anti-IL-18 antibody, the individual's serum M-protein is reduced by less than or equal to 49%, as measured by SPEP. The method of any one of claims 1 to 42, wherein after one or more administrations of the anti-IL-18 antibody, the individual's serum M-protein is reduced as measured by SPEP. The method of any one of claims 1 to 46, wherein after one or more administrations of the anti-IL-18 antibody, the subject's M-protein becomes stable as measured by SPEP. The method of any one of claims 1 to 47, wherein the individual achieves an improvement in the Eastern Cooperative Oncology Group Performance Status (ECOG PS) score. The method of any one of claims 1 to 48, wherein the individual has undetectable levels of serum or bone marrow free or total IL-18 about 28 days after administration of the anti-IL-18 antibody. The method of any one of claims 1 to 49, wherein the individual has undetectable levels of serum or bone marrow free IL-18 about 28 days after administration of the anti-IL-18 antibody. The method of any one of claims 1 to 50, wherein the individual has undetectable levels of serum or bone marrow free or total IL-18 about 112 days after administration of the first dose of the anti-IL-18 antibody . The method of claims 1 to 50, wherein the individual has undetectable levels of serum free IL-18 about 112 days after administration of the anti-IL-18 antibody. The method of any one of claims 1 to 50, wherein the individual has a reduced level of serum or bone marrow free or total IL-18 about 28 days after administration of the anti-IL-18 antibody. The method of any one of claims 1 to 50, wherein the individual has a reduced level of serum or bone marrow free IL-18 about 112 days after administration of the anti-IL-18 antibody. A kit for the method of any one of claims 1 to 54, comprising an anti-IL-18 antibody and reagents for performing the method, optionally wherein the antibody comprises the following six CDRs: (a) HCDR1 having the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 having the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 having the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 having the amino acid sequence of SEQ ID NO: 126; (e) LCDR2 having the amino acid sequence of SEQ ID NO: 127; and (f) LCDR3 having the 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 at least 90% identical to the entire sequence of SEQ ID NO: 121, and having an amino acid sequence at least 90% identical to the entire sequence of SEQ ID NO: 125 The VL domain of the sequence.

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