Methods and treatments for adult-onset Still's disease and systemic-onset juvenile idiopathic arthritis involving antibodies against IL-18 - Patent Application 20070123333

Abstract

The present disclosure relates to a method of treating Adult-onset Still's Disease (AOSD) or Systemic-onset Juvenile Idiopathic Arthritis (SoJIA), optionally accompanied by elevated IL-18 levels, comprising administering to a human subject diagnosed with AOSD or SoJIA an effective amount of an anti-IL-18 antibody at a particular dosage.

Description

[Technical field]

[0001]

[0001] This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on December 13, 2021, is named 01118-0060-00PCT_SL_ST25.txt and is 109,128 bytes in size.

[0002] The present disclosure relates to methods of treating subjects with adult-onset Still's disease (AOSD) or systemic-onset juvenile idiopathic arthritis (SoJIA) by administering a neutralizing anti-interleukin-18 (IL-18) antibody. [Background technology]

[0002]

[0003] Adult-onset Still's disease is an inflammatory disorder characterized by daily fever, arthritis, and a transient rash. Adult-onset Still's disease was first described in children by George Still in 1897, but was later described in adult patients with features similar to those of children with juvenile idiopathic arthritis and who did not meet the criteria for classical rheumatoid arthritis (Bywaters, E. G., Ann Rheum Dis. 30(2), pp. 121-133 (1971)). Adult-onset Still's disease is a rare disease. A retrospective French study estimated the annual incidence of AOSD at 0.16 cases per 100,000, with equal distribution between men and women (Magadur-Joly G et al., Ann Rheum Dis. 54(7):587 (1995)). It is estimated that there are approximately 3,500-7,000 AOSD patients in the United States (Gerfaud-Valentin M et al., Medicine (Baltimore) 93(2):91 (2014)). A bimodal age distribution is seen, with one peak at 15-25 years and a second peak at 36-46 years (Magadur-Joly G et al., Ann Rheum Dis. 54(7):587 (1995)). However, patients over 70 years of age have also been reported (Steffe LA & Cooke CL, JAMA 249(15):2062 (1983)).

[0003]

[0004] No targeted therapy for AOSD is currently approved in the United States. Treatment is tailored to disease stage, symptoms, and the presence of end-organ damage, as well as minimization of corticosteroid side effects. Initial treatment typically employs nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. Refractory patients are treated with immunosuppressants, including methotrexate. Patients who remain refractory may be empirically treated with biologic agents, including anti-TNF antibodies (adalimumab), anakinra (anti-IL-1), or tocilizumab (anti-IL-6). Patients must be closely monitored for the development of macrophage activation syndrome (MAS). While many patients may derive at least partial benefit from this approach, others may remain refractory or partially refractory (Jamilloux, Y. et al., Therapeutics and Clinical Risk Management (2014)). Thus, there is a need for new targeted therapies.

[0004]

[0005] The clinical course of AOSD can be classified into three main patterns: monophasic (or monocyclic), intermittent, and chronic, with approximately one-third of patients falling into each category (Kontzias, A. and Efthimiou, P., Drugs 68(3):319 (2008); Gerfaud-Valentin M et al., Medicine (Baltimore) 93(2):91 (2014)). Patients with monophasic or intermittent disease often progress to a chronic articular pattern (Kontzias, A. and Efthimiou, P., Drugs 68(3):319 (2008); Gerfaud-Valentin M et al., Medicine (Baltimore) 93(2):91 (2014); Fautrel, B., Best Pract. Res. Clin. Rheumatol. 22(5):773 (2008)).

[0005]

[0006] Most patients with active AOSD have fever, transient rash, joint pain, and arthritis. The most commonly involved joints are the knee, wrist, ankle, elbow, proximal interphalangeal joint, and shoulder (Elkon, KB, et al., Arthritis Rheum. 25(6):647 (1982)). Many patients also have myalgia (Pouchot, J, et al., Medicine (Baltimore) 70(2):118 (1991)), pharyngitis (Nguyen, KH, and Weisman MH, J Rheumatol. 24(3):592 (1997)), and liver disease (Gerfaud-Valentin, M, et al., Autoimmun Rev. Jul;13(7):708-722 (2014)). Fulminant hepatic failure has also been reported in AOSD (Dino, O. et al., J Rheumatol. 23(4):784-785 (1996)). Cardiopulmonary disease (Gerfaud-Valentin, M. et al., Autoimmun Rev. Jul; 13(7):708-722 (2014); Cheema, GS. and Quismorio, FP. Jr. Curr Opin Pulm Med. 5(5):305 (1999)), lymphadenopathy (Gerfaud-Valentin, M. et al., Autoimmun Rev. Jul; 13(7):708-722 (2014)), and splenomegaly (Gerfaud-Valentin, M. et al., Autoimmun Rev. Jul; 13(7):708-722 (2014)) may also be present.

[0006]

[0007] Adult-onset Still's disease may be complicated by macrophage activation syndrome (MAS), also called hemophagocytic lymphohistiocytosis (HLH), in 12%-19% of patients (Arlet, JB et al., Ann Rheum Dis. 65(12):1596 (2006); Bae, CB et al., Medicine (Baltimore) 94(4):e451 (2015); Hot, A et al., Medicine (Baltimore) 89(1):37 (2010)). Other blood disorders that may be associated with AOSD include microangiopathic hemolytic anemia associated with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (Diamond, JR, GJ Nephrol. 10(5):253 (1997); Perez, MG and Rodwig, FR Jr., South Med J. 96(1):46 (2003); Arlet, JB et al., Ann Rheum Dis. 65(12):1596 (2006)). Abdominal pain may occur in up to half of AOSD patients (Gerfaud-Valentin, M. et al., Autoimmun Rev. Jul;13(7):708-722 (2014)), and symptoms may be associated with lymphadenitis, aseptic peritonitis, or acute pancreatitis (Fautrel, B., Best Pract Res Clin Rheumatol. 22(5):773 (2008)). Adult-onset Still's disease is diagnosed in the presence of five or more diagnostic criteria, with two or more being major criteria, and in the absence of exclusion criteria (Jamilloux, Y. et al., Therapeutics and Clinical Risk Management Dec. (2014)). Major criteria are fever >39°C for >2 weeks; arthralgia or arthritis for >2 weeks; typical nonpruritic salmon rash; leukocytosis >10,000 / mm 3; and granulocytes >80% (Jamilloux, Y et al., Therapeutics and Clinical Risk Management Dec. (2014)). Minor diagnostic criteria are sore throat; lymphadenopathy; splenomegaly; abnormal liver function tests; and negative tests for antinuclear antibodies and rheumatoid factor (Jamilloux, Y et al., Therapeutics and Clinical Risk Management Dec. (2014)). Exclusion criteria are infections; malignancies; and other rheumatic diseases (vasculitis) (Jamilloux, Y et al., Therapeutics and Clinical Risk Management Dec. (2014)).

[0007]

[0008] Some of the treatment goals for AOSD are: control of the physical signs and symptoms of inflammation (fever, rash, morning stiffness, joint pain, and swelling); control of laboratory indicators of inflammation; prevention of end-organ damage, including joint damage and other major organ complications; and minimization of the risk of side effects of treatment, including short-term and long-term side effects of glucocorticoids.

[0008]

[0009] Systemic-onset juvenile idiopathic arthritis (SoJIA) is similar to AOSD but differs in classification criteria (Silva, JR, and Brito, I, Acta Reumatol Port. 45(2):150-151 (2020)). It has been argued that SoJIA and AOSD are the same disease, just occurring in different age groups (Silva, JR, and Brito, I, Acta Reumatol Port. 45(2):150-151 (2020)). SoJIA is a subset of juvenile idiopathic arthritis characterized by more severe extra-articular symptoms (fever, skin rash). See NIH Genetic and Rare Diseases Information Center, Systemic onset juvenile idiopathic arthritis (available at https: / / rarediseases.info.nih.gov / diseases / 10966 / systemic-onset-juvenile-idiopathic-arthritis) (last accessed December 14, 2021). SoJIA represents 10-11% of cases of juvenile idiopathic arthritis. Ibid. Onset usually occurs between 3-5 years of age. Ibid. Clinical signs include fever with cyclic fluctuations in temperature and peaks of 39°C or higher over a 24-hour period, which is accompanied by a transient skin rash and generalized lupus or urticarial lesions. Ibid. Another symptom is arthritis. Ibid. The number of body parts affected by arthritis varies, but small and large joints are affected almost symmetrically. Ibid. Some patients may also have adenopathy and / or hepatosplenomegaly. Ibid. Other symptoms such as pericarditis, pleural effusion, or serous peritonitis with abdominal pain may be present. Ibid. SoJIA patients typically have severe inflammatory disease with greatly increased ferritin levels and decreased percentage of glycated ferritin. Ibid. Physicians often diagnose the disease using the "clinical triad": daily fever lasting more than two weeks, arthritis, and a skin rash. See Petty, R, et al., J. Rheumatol. 31(2) 390-392 (2004). If the patient does not have a skin rash, the presence of adenopathy, hepatosplenomegaly, or serous effusion can also support the diagnosis.

[0009]

[0010] IL-18 is a pro-inflammatory cytokine that plays a role in both innate and adaptive immune responses. In many AOSD patients, IL-18 is significantly elevated. In active AOSD, IL-18 concentrations are >100,000 pg / ml and have been found to correlate with disease severity (Kudela, H. et al., BMC Rheum 3:4 (2019)). The elevation appears to be more specific for AOSD than other systemic rheumatic diseases (Kawashima, M. et al., Arthritis Rheum. 44(3):550 (2001); Kudela, H. et al., BMC Rheum 3:4 (2019)).

[0010]

[0011] A 12-week study of 23 AOSD patients treated with tadekinig alfa (IL-18 binding protein [IL-18 BP]) showed modest efficacy in approximately half of treated patients, suggesting that targeting IL-18 may be an effective treatment strategy in AOSD (Gabay, C et al. Ann Rheum Dis. Jun;77(6):840-847 (2018)). Limitations in the study design, as well as the route of administration (SC) and PK (relatively short t1 / 2) of tadekinig alfa, may have limited the efficacy seen in this trial. Summary of the Invention

[0011]

[0017] The present disclosure includes, for example, any one of the following embodiments or combinations of the following embodiments.

[0012] Embodiment 1. A method of treating Adult-onset Still's Disease (AOSD) or Systemic-onset Juvenile Idiopathic Arthritis (SoJIA), comprising administering to a human subject diagnosed with AOSD or SoJIA an effective amount of an anti-IL-18 antibody, wherein the anti-IL-18 antibody has 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) an HCDR3 having the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 having the amino acid sequence of SEQ ID NO: 126; (e) an LCDR2 having the amino acid sequence of SEQ ID NO: 127; and (f) LCDR3 having the amino acid sequence of SEQ ID NO: 128 wherein the anti-IL-18 antibody is administered at a dose of 4 mg / kg, 7 mg / kg, or 14 mg / kg.

[0013] Embodiment 2. The method of embodiment 1, wherein the subject is diagnosed with AOSD based on having five or more of the following criteria, two of which are major criteria: (a) Major criteria i. Fever >39°C for more than one week ii. Joint pain or arthritis lasting for more than 2 weeks iii. Typical rash iv. >10,000 mm of white blood cells with >80% polymorphonuclear cells 3 (b) Minor criteria v. Sore throat vi. Recent onset of significant lymphadenopathy vii. Hepatomegaly or splenomegaly viii. Abnormal liver function tests ix. Antinuclear antibody (IF) and rheumatoid factor (IgM) tests were negative.

[0014] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the subject reports a recurrence of fever >38°C within the last 5 days of the Screening and Baseline visits.

[0015] Embodiment 4. The method of any one of embodiments 1-3, wherein if the subject is being treated with NSAIDs, the subject has been receiving a stable dose for at least 48 hours prior to the baseline visit.

[0016] Embodiment 5. The method of any one of embodiments 1-4, wherein if the subject is receiving treatment with a glucocorticoid, the subject has been receiving a stable dose for at least 48 hours prior to the baseline visit.

[0017] Embodiment 6. The method of any one of embodiments 1-5, wherein if the subject is being treated with a conventional DMARD, the subject has been receiving a stable dose for at least 12 weeks prior to the baseline visit.

[0018] Embodiment 7. The method of any one of embodiments 1-6, wherein if the subject is receiving treatment with a biologic DMARD, the subject has undergone a required drug-off period prior to the Baseline Visit, and the required drug-off period is as follows: a) Anakinra - 1 week; b) etanercept, rilonacept - 4 weeks; c) adalimumab, certolizumab, infliximab, golimumab, abatacept, tocilizumab, and canakinumab - 8 weeks; and d) Rituximab - 36 weeks.

[0019] Embodiment 8. The method of any one of embodiments 1-7, wherein the subject does not have a serum creatinine concentration >1.5 mg / dl.

[0020] Embodiment 9. The method of any one of embodiments 1-8, wherein the subject does not have hemoglobin≦10 g / dl, neutrophils≦1,500 / μl, and / or platelets≦75,000 / μl.

[0021] Embodiment 10. The method of any one of embodiments 1 or 3-9, including a method of treating SoJIA.

[0022] Embodiment 11. The method of any one of embodiments 1-10, wherein the subject has elevated free or total serum IL-18 levels.

[0023] Embodiment 12. The method of any one of embodiments 1-11, wherein the level of serum IL-18 is measured prior to administration of the anti-IL-18 antibody.

[0024] Embodiment 13. The method of any one of embodiments 1 to 12, wherein the level of serum IL-18 is measured after administration of an anti-IL-18 antibody, optionally as a marker of efficacy of the treatment.

[0025] Embodiment 14. The method of any one of embodiments 1-13, wherein the level of serum IL-18 is elevated compared to the level in a subject without AOSD or SoJIA, or compared to a negative control.

[0026] Embodiment 15. The method of any one of embodiments 1 to 14, wherein the subject's serum IL-18 level is measured after administration of an anti-IL-18 antibody as a marker of efficacy of the treatment.

[0027] Embodiment 16. The method of any one of embodiments 1-15, wherein the level of serum IL-18 is free IL-18, and optionally the level of free IL-18 is calculated.

[0028] Embodiment 17 The method of any one of embodiments 1-15, wherein the level of serum IL-18 is total IL-18.

[0029] Embodiment 18. The method of any one of embodiments 1-16, wherein the subject has elevated serum free IL-18.

[0030] Embodiment 19. The method of any one of embodiments 1-15 or 17, wherein the subject has elevated serum total IL-18.

[0031] Embodiment 20. The method of any one of embodiments 1-19, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence that is at least 90% identical to the complete sequence of SEQ ID NO:121.

[0032] Embodiment 21. The method of any one of embodiments 1-20, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence identical to the complete sequence of SEQ ID NO:121.

[0033] Embodiment 22. The method of any one of embodiments 1 to 21, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence that is at least 90% identical to the complete sequence of SEQ ID NO:125.

[0034] Embodiment 23 The method of any one of embodiments 1-22, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence identical to the complete sequence of SEQ ID NO:125.

[0035] Embodiment 24. The method of any one of embodiments 1 to 23, wherein the anti-IL-18 antibody comprises an antibody VH domain and an antibody VL domain, wherein the amino acid sequence of the antibody VH domain is at least 90% identical to the complete sequence of SEQ ID NO: 121, and the antibody VL domain is at least 90% identical to the complete sequence of SEQ ID NO: 125.

[0036] Embodiment 25. The method of any one of embodiments 1-24, wherein the anti-IL-18 antibody is administered in the form of a pharma- ceutically acceptable composition.

[0037] Embodiment 26 The method of any one of embodiments 1-25, wherein the anti-IL-18 antibody is administered for at least 16 weeks.

[0038] Embodiment 27 The method of any one of embodiments 1-26, wherein the anti-IL-18 antibody is administered intravenously.

[0039] Embodiment 28 The method of any one of embodiments 1-26, wherein the anti-IL-18 antibody is administered subcutaneously.

[0040] Embodiment 29. The method of any one of embodiments 1-28, 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.

[0041] Embodiment 30 The method of any one of embodiments 1-29, wherein the subject achieves resolution of fever.

[0042] Embodiment 31 The method of any one of embodiments 1-30, wherein the subject achieves a reduction in CRP.

[0043] Embodiment 32 The method of any one of embodiments 1-31, wherein the subject achieves a ≧50% reduction in CRP from baseline by week 4.

[0044] Embodiment 33 The method of any one of embodiments 1-32, wherein the subject achieves a ≧50% reduction in CRP from baseline by week 12.

[0045] Embodiment 34 The method of any one of embodiments 1-33, wherein the subject achieves a reduction in serum IL-18 levels.

[0046] Embodiment 35 The method of any one of embodiments 1-34, wherein the subject achieves a reduction in serum total IL-18 levels.

[0047] Embodiment 36 The method of any one of embodiments 1-34, wherein the subject achieves a reduction in serum free IL-18 levels.

[0048] Embodiment 37. The method of any one of embodiments 1-36, wherein the subject has an undetectable level of serum IL-18 about 4 weeks after administration of the anti-IL-18 antibody.

[0049] Embodiment 38. The method of any one of embodiments 1-37, wherein the subject has an undetectable level of serum IL-18 at about 12 weeks after administration of the anti-IL-18 antibody.

[0050] Embodiment 39. The method of any one of embodiments 1-38, wherein the subject has an undetectable level of serum total IL-18 about 4 weeks after administration of the anti-IL-18 antibody.

[0051] Embodiment 40. The method of any one of embodiments 1-39, wherein the subject has an undetectable level of serum total IL-18 at about 12 weeks after administration of the anti-IL-18 antibody.

[0052] Embodiment 41. The method of any one of embodiments 1-38, wherein the subject has an undetectable level of serum free IL-18 about 4 weeks after administration of the anti-IL-18 antibody.

[0053] Embodiment 42. The method of any one of embodiments 1-39, wherein the subject has an undetectable level of serum free IL-18 at about 12 weeks after administration of the anti-IL-18 antibody.

[0054] Embodiment 43. The method of any one of embodiments 1 to 42, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by Physician and / or Patient Global Assessment of Disease Activity assessed by a Visual Analogue Scale (VAS).

[0055] Embodiment 44. The method of any one of embodiments 1-43, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by physician and / or patient global assessment of disease activity assessed by visual analog scale (VAS) at least about 4 weeks after administration of the anti-IL-18 antibody.

[0056] Embodiment 45. The method of any one of embodiments 1-44, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by physician and / or patient global assessment of disease activity assessed by visual analog scale (VAS) at least about 12 weeks after administration of the anti-IL-18 antibody.

[0057] Embodiment 46 The method of any one of embodiments 1-45, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a modified Pouchot score.

[0058] Embodiment 47. The method of any one of embodiments 1-46, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA, as assessed using a modified Pouchot score, about 4 weeks after administration of the anti-IL-18 antibody.

[0059] Embodiment 48. The method of any one of embodiments 1-47, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA, as assessed using a modified Pouchot score, at about 12 weeks after administration of the anti-IL-18 antibody.

[0060] Embodiment 49. The method of any one of embodiments 1-48, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using the DAS28-CRP score.

[0061] Embodiment 50. The method of any one of embodiments 1-49, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA, as assessed using the DAS28-CRP score, about 4 weeks after administration of the anti-IL-18 antibody.

[0062] Embodiment 51. The method of any one of embodiments 1-50, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA, as assessed using the DAS28-CRP score, about 12 weeks after administration of the anti-IL-18 antibody.

[0063] Embodiment 52 The method of any one of embodiments 1-51, wherein the subject experiences a decrease in serum ferritin.

[0064] Embodiment 53 The method of any one of embodiments 1-52, wherein the subject experiences a decrease in serum ferritin about 4 weeks after administration of the anti-IL-18 antibody.

[0065] Embodiment 54 The method of any one of embodiments 1-53, wherein the subject experiences a decrease in serum ferritin at about 12 weeks after administration of the anti-IL-18 antibody.

[0066] Embodiment 55. The method of any one of embodiments 1-54, wherein the subject experiences a decrease in erythrocyte sedimentation rate (ESR).

[0067] Embodiment 56 The method of any one of embodiments 1-55, wherein the subject experiences a decrease in erythrocyte sedimentation rate (ESR) about 4 weeks after administration of the anti-IL-18 antibody.

[0068] Embodiment 57. The method of any one of embodiments 1-56, wherein the subject experiences a decrease in erythrocyte sedimentation rate (ESR) about 12 weeks after administration of the anti-IL-18 antibody.

[0069] Embodiment 58. The method of any one of embodiments 1 to 57, further comprising administering one or more additional therapeutically active agents.

[0070] Embodiment 59. The method of embodiment 58, wherein the one or more additional therapeutically active agents comprise at least one of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, systemic glucocorticoids, and conventional systemic disease-modifying anti-rheumatic drugs (DMARDs).

[0071] Embodiment 60 The method of embodiment 59, wherein the conventional systemic disease-modifying antirheumatic drug (DMARD) is methotrexate.

[0072] Embodiment 61 The method of embodiment 59, wherein the corticosteroid is prednisone.

[0073] Embodiment 62. A kit for use in the method of any one of embodiments 1 to 61, comprising an anti-IL-18 antibody and reagents for carrying out the method. [Brief description of the drawings]

[0074] [Figure 1]

[0012] Figure 1 shows a major inflammatory marker-C-reactive protein (CRP) measured in mg / L per visit. The Y-axis is the CRP concentration measured in mg / L. The X-axis refers to time. Each line refers to data from one patient. Each patient is also assigned a number. Each number next to each data point on the line graph indicates the CRP concentration (mg / L) for that patient at that time. "V" refers to "visit" and the number after "V" refers to the visit number. For example, "V3" refers to visit 3. "Early Term" refers to early termination. "F / U" refers to follow-up visit. Week on the X-axis (e.g., "Wk 1") refers to the assessment week shown in Table 1, Assessment Schedule, herein. [Figure 2A] FIG. 2A shows the key inflammatory marker-ferritin measured in ng / L at each visit for two patients. The Y-axis is ferritin concentration (ng / mL). The X-axis refers to time. Each line refers to data from one patient. Each patient is also assigned a number. Each number next to each data point on the line graph indicates the ferritin concentration (ng / L) for that patient at that time. "V" refers to "visit" and the number after "V" refers to the visit number. For example, "V3" refers to visit 3. The week on the X-axis (e.g., "Wk 1") refers to the assessment week shown in Table 1, Assessment Schedule, herein. "Early Term" refers to early termination. "F / U" refers to follow-up visit. [Figure 2B]FIG. 2B illustrates the key inflammatory marker-ferritin measured in ng / L per visit for one patient, patient 012-01. The Y-axis is ferritin concentration (ng / mL). The X-axis refers to time. The lines refer to data from one patient. The patients are assigned a number. Each number next to each data point on the line graph indicates the patient's ferritin concentration (ng / L) at that time. "V" refers to "visit" and the number after "V" refers to the number of visits. For example, "V3" refers to visit 3. The week on the X-axis (e.g., "Wk 1") refers to the assessment week shown in Table 1, Evaluation Schedule, herein. The data for patient 012-01 is shown separately in this figure because the ferritin concentration of that patient was higher than the ferritin concentrations of the other patients whose data are shown in FIG. 2A, necessitating a different scale for the Y-axis. [Diagram 3]

[0014] Figure 1. Key inflammatory markers by visit - modified Pouchot score. The Y-axis is modified Pouchot score. The X-axis refers to time. Each line refers to data from one patient. Each patient is also assigned a number. "V" refers to "visit" and the number after the "V" refers to the visit number. For example, "V3" refers to visit 3. "ET" refers to early termination. Week on the X-axis (e.g., "Wk 1") refers to the assessment week shown in Table 1, Evaluation Schedule, herein. [Figure 4]

[0015] Figure 1. Key inflammatory markers measured on a 100mm visual analog scale (VAS) at each visit - Physician Global Assessment (PhGA). The Y-axis is PhGA score measured on a 100mm VAS. The X-axis refers to time. Each line refers to data from one patient. Each patient is also assigned a number. "V" refers to "visit" and the number after "V" refers to the visit number. For example, "V3" refers to visit 3. "ET" refers to early termination. Week on the X-axis (e.g., "Wk 1") refers to the assessment week shown in Table 1, Evaluation Schedule, herein. [Diagram 5]

[0016] Figure 1. Key inflammatory markers measured on a 100mm visual analog scale (VAS) at each visit - Patient Global Assessment (PtGA). The Y-axis is PtGA score measured on a 100mm VAS. The X-axis refers to time. Each line refers to data from one patient. Each patient is also assigned a number. Each number next to each data point on the line graph indicates the PtGA score for that patient at that time. "V" refers to "visit" and the number after "V" refers to the number of visits. For example, "V3" refers to visit 3. "ET" refers to early termination. Week on the X-axis (e.g., "Wk 1") refers to the assessment week shown in Table 1, Assessment Schedule, herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075]

[0018] The following definitions are provided to facilitate the understanding of the invention. They are not intended to limit the invention in any way.

[0076] definition For the purposes of the present invention, "a" or "an" entity refers to one or more of that entity; for example, "a cDNA" refers to one or more cDNAs or at least one cDNA. Therefore, the terms "a" or "an", "one or more" and "at least one" may be used interchangeably herein. It should also be noted that the terms "comprising", "including" and "having" may be used interchangeably. Furthermore, a compound "selected from the group consisting of" refers to one or more of the compounds in the following list, including mixtures (i.e., combinations) of two or more of the compounds. According to the present invention, an "isolated" or "biologically pure" molecule is a compound that has been removed from its natural environment. Therefore, the terms "isolated" and "biologically pure" do not necessarily reflect how purified a compound has been. An isolated compound of the present invention may be obtained from its natural source, may be made using laboratory synthesis techniques, or may be produced by any such chemical synthesis route.

[0077] "IL-18" or "Interleukin-18" or "Interferon-gamma-inducing factor" or "IFN-γ-inducing factor" refers to a proinflammatory cytokine encoded by the IL18 gene that belongs to the IL-1 family of cytokines. Like IL-1β, it is synthesized as an inactive precursor called pro-IL-18 that is activated by cleavage by caspase-1. Pro-IL-18 is present in healthy cells and is constitutively expressed by monocytes and epithelial cells. IL-18 plays a role in stimulating both adaptive and innate immune responses.

[0078]

[0021] "Elevated IL-18" as used herein refers to a level of total IL-18 detected in a subject that is higher than a normal control. A normal control can be determined by one skilled in the art as applicable to a particular situation. In some cases, a normal control is an industry standard agreed upon by one skilled in the art as a typical level or range of levels for individuals without an IL-18-associated condition. In some cases, a normal control is a reference level of IL-18 from the same individual taken at one time point, and whether a subject has elevated IL-18 is determined based on a sample from the same individual taken at a different time point, typically a later time point.

[0079]

[0022] "Free IL-18" or "free (active) IL-18" as used herein refers to the active, unbound form of IL-18. In humans, free IL-18 is neutralized (inactivated) by IL-18BP. IL-18BP binds to IL-18 and inhibits its activity by preventing its interaction with IL-18Rα.

[0080] "Bound IL-18" and the like refers to IL-18 bound to a natural ligand, where the natural ligand is optionally IL-18Rα or IL-18BP. Free IL-18 can be calculated according to known methods, for example Palladino et al. (2012) J. Neuroinflammation 9 (206).

[0081]

[0024] "Total IL-18" and the like refers to the total amount of free IL-18 and bound IL-18.

[0082] "Serum" or "circulating" IL-18 is IL-18 that is found in serum.

[0083]

[0026] "Undetectable levels of serum IL-18" refers to levels of IL-18 below the level of quantification of an assay that measures IL-18.

[0084]

[0027] The term "antibody" is used in the broadest sense herein and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity. As used herein, the term refers to a molecule comprising at least complementarity determining region (CDR)1, CDR2, and CDR3 of a heavy chain, and at least CDR1, CDR2, and CDR3 of a light chain, which can bind 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 specified, a "set of CDRs" includes HCDRs and LCDRs. The term antibody includes, but is not limited to, fragments capable of binding to an antigen, such as Fv, single chain Fv (scFv), Fab, Fab', and (Fab')2. The term antibody also includes, but is not limited to, chimeric antibodies, humanized antibodies, human antibodies, and antibodies of various species such as mouse, cynomolgus monkey, etc.

[0085] The term "heavy chain" refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term "full-length heavy chain" refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0086] The term "heavy chain variable region" or "VH domain" refers to the region of a heavy chain that comprises heavy chain complementarity determining region (CDR) 1, 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, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.).

[0087] The term "light chain" refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term "full-length light chain" refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0088] The term "light chain variable region" or "VL domain" refers to a region that includes light chain CDR1, FR2, HVR2, FR3, and HVR3. In some embodiments, the light chain variable region also includes FR1 and / or FR4. In some embodiments, light chain CDR1 corresponds to Kabat residues 24-34, light chain CDR2 corresponds to Kabat residues 50-56, and light chain CDR3 corresponds to Kabat residues 89-97. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.).

[0089]

[0032] "Chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remaining portions of the heavy and / or light chain are derived from a different source or species. In some embodiments, a chimeric antibody refers to an antibody that comprises at least one variable region derived from a first species (e.g., mouse, rat, cynomolgus monkey, etc.) and at least one constant region derived from a second species (e.g., human, cynomolgus monkey, etc.). In some embodiments, a chimeric antibody comprises at least one mouse variable region and at least one human constant region. In some embodiments, a chimeric antibody comprises at least one cynomolgus monkey variable region and at least one human constant region. In some embodiments, all of the variable regions of the chimeric antibody are derived from a first species, and all of the constant regions of the chimeric antibody are derived from a second species.

[0090]

[0033] "Humanized antibody" refers to an antibody in which at least one amino acid in the framework region of a non-human variable region is replaced with the corresponding amino acid from a human variable region. In some embodiments, a humanized antibody comprises at least one human constant region or a fragment thereof. In some embodiments, a humanized antibody is a Fab, scFv, (Fab')2, etc.

[0091]

[0034] "Human antibody," as used herein, refers to antibodies produced in humans, antibodies produced in non-human animals that contain human immunoglobulin genes, such as XenoMouse®, and antibodies selected using in vitro methods, such as phage display, whose antibody repertoire is based on human immunoglobulin sequences.

[0092] The term "leader sequence" refers to a sequence of amino acid residues located at the N-terminus of a polypeptide that facilitates secretion of the polypeptide from a mammalian cell. The leader sequence may be cleaved upon export of the polypeptide from the mammalian cell to form the mature protein. Leader sequences may be natural or synthetic and may be heterologous or homologous to the protein to which it binds.

[0093]

[0036] "Percent (%) amino acid sequence identity" and "homology" with respect to a peptide, polypeptide, or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without considering conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of 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. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared.

[0094]

[0037] The term "inhibition" or "inhibiting" refers to the reduction or cessation of any event (such as protein ligand binding), or the reduction or cessation of any phenotypic characteristic, or the reduction or cessation of the incidence, degree, or likelihood of that characteristic. "Reducing" or "inhibiting" is the reduction, reduction, or cessation of an activity, function, and / or amount compared to a reference. Inhibition or reduction need not be complete. For example, in certain embodiments, "reducing" or "inhibiting" refers to the ability to effect an overall reduction of 20% or more. In another embodiment, "reducing" or "inhibiting" refers to the ability to effect an overall reduction of 50% or more. In yet another embodiment, "reducing" or "inhibiting" refers to the ability to effect an overall reduction of 75%, 85%, 90%, 95% or more.

[0095]

[0038] "Sample" or "subject sample" or "biological sample" generally refers to a sample that can be tested for a particular molecule. Samples can include, but are not limited to, cells, bone marrow, bodily fluids (including blood, serum, plasma, urine, saliva, stool, tears, pleural fluid, etc.).

[0096]

[0039] The terms "agent" and "test compound" are used interchangeably herein and refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological material such as bacteria, plants, fungi, or animal (especially mammalian) cells or tissues. Biological macromolecules include siRNAs, shRNAs, antisense oligonucleotides, peptides, peptide / DNA complexes, and any nucleic acid-based molecule that exhibits the ability to modulate the activity of the SNP containing nucleic acids described herein, or their encoded proteins.

[0097]

[0040] A "subject" may be a mammal. In any of the embodiments involving a subject, the subject may be a human. In any of the embodiments involving a subject, the subject may be a cow, a pig, a monkey, a sheep, a dog, a cat, a fish, or a poultry.

[0098]

[0041] A "pediatric" subject, as used herein, is a human under the age of 18, whereas an "adult" subject is 18 or older.

[0099]

[0042] The term "pharmaceutically acceptable composition" can refer to a composition that contains an anti-IL-18 antibody in a formulation with a wide variety of pharma- ceutically acceptable carriers.

[0100]

[0043] The term "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation or composition, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, and / or preservatives.

[0101]

[0044] "Treatment" or "treat" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder, as well as those prone to have the disorder, or those in which the disorder is to be prevented. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of the disease, a stabilized (i.e., not worsening) state of the disease, a delay or slowing of disease progression, an improvement or palliation of the disease state, and remission (whether partial or complete remission). "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.

[0102]

[0045] The term "effective amount" or "therapeutically effective amount" refers to an amount of a drug effective in treating a disease or disorder of interest to partially or completely alleviate one or more symptoms. In some embodiments, an effective amount refers to an amount, at dosages and for periods of time necessary, effective to achieve a desired therapeutic or prophylactic result.

[0103] "Adult-onset Still's disease" or "AOSD" can be diagnosed in several different ways. One accepted method of diagnosing AOSD is by the presence of fever >39°C for more than 1 week; joint pain or arthritis for more than 2 weeks; a typical rash; white blood cells >10,000 mm with >80% polymorphonuclear cells; 3 sore throat; recent onset of significant lymphadenopathy; hepatomegaly or splenomegaly; abnormal liver function tests; negative antinuclear antibody (IF) and rheumatoid factor (IgM) tests; fever >39°C for >1 week; arthralgia or arthritis for >2 weeks; typical rash; or white blood cells >10,000 mm with >80% polymorphonuclear cells 3 Based on the classification criteria defined as having at least two of the following:

[0104]

[0047] The term "PtGA" or "Patient Global Assessment of Disease Activity" measured based on a visual analog scale (VAS) is a measure of a patient's disease activity assessed by the patient on a 100mm scale. For example, some Patient Global Assessment of Disease Activity scales ask patients to assess their disease activity based on questions such as "Look at different aspects of the AOSD that affect you and rate how well you are doing on the following scale" (0-100). A score of "0mm" often means that the patient is doing very well / no evidence of disease, while a score of "100mm" indicates that the patient is doing very poorly / has very severe disease activity.

[0105]

[0048] The term "PhGA" or "Physician Global Assessment of Disease Activity" measured on a visual analog scale (VAS) is a measure of a patient's disease activity as assessed by a physician on a 100mm scale. A score of "0mm" often means that the patient is doing much better / has no evidence of disease, and a score of "100mm" indicates that the patient is doing much worse / has very severe disease activity. The assessing physician should not be aware of the individual PtGA when making his or her own patient assessment.

[0106] "CRP" refers to C-reactive protein, a blood protein. CRP is made in the liver and sent to the bloodstream in response to inflammation. CRP is measured in mg / L. CRP levels rise and fall with levels of inflammation, with greater inflammation corresponding to higher CRP levels. Results are typically compared to normal ranges, although normal range values ​​may vary slightly from laboratory to laboratory.

[0107]

[0050] "DAS28-CRP" or "Disease Activity Score 28 for Rheumatoid Arthritis with CRP" refers to a score calculated based on information about the following disease variables: swollen and tender joint counts (TJC28 and SJC28) assessed using a 28 joint count; PtGA (Patient Global Assessment of Disease Activity) measured on a 100 mm VAS (visual analog scale); and CRP measured in mg / L. Using this information, the DAS28-CRP score is calculated using the following formula: 0.56 x sqrt(TJC28) + 0.28 x sqrt(SJC28) + 0.36 x ln(CRP+1) + 0.014 x PtGA + 0.96. DAS28 scores range from 0 to 10, with higher scores indicating more severe current activity of the disease. The DAS28 score can also be classified into disease activity states according to cutoff values: high disease activity: >5.1; moderate disease activity: >3.2 to <5.1; low disease activity: >2.6 to <3.2; remission: <2.6.

[0108] The term "corticosteroid" is a type of anti-inflammatory drug. Corticosteroids are man-made drugs that closely resemble cortisol, a hormone that is naturally produced by the adrenal glands. Some examples of corticosteroids include cortisone and prednisone. Glucocorticosteroids (also called glucocorticoids) are a type of corticosteroid.

[0109]

[0052] The term "disease-modifying antirheumatic drug" or "DMARD" refers to a class of drugs indicated for the treatment of inflammatory arthritis, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, and can also be used in the treatment of other disorders, such as connective tissue disease, systemic sclerosis, systemic lupus erythematosus, and Sjogren's syndrome. DMARDs can also be used in the treatment of inflammatory myositis, vasculitis, uveitis, inflammatory bowel disease, and in the treatment of some types of cancer. DMARDs are immunosuppressive or immunomodulatory. Each DMARD has a unique mechanism of action, but all ultimately interfere with any one of the many clinical pathways of the inflammatory cascade. DMARDs can be conventional or biologic DMARDs. Common conventional DMARDs include methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. Biologic DMARDs include anakinra, infliximab, adalimumab, certolizumab, canakinumab, golimumab, etanercept, rilonacept, abatacept, rituximab, tocilizumab, and others.

[0110]

[0053] The term "erythrocyte sedimentation rate" or "ESR" refers to the results of a blood test that helps detect inflammation. The test measures the rate at which red blood cells (erythrocytes) fall (sedimentation) in a blood sample placed in a tall, upright tube. An increase in ESR indicates inflammation. The results are measured in millimeters of plasma left at the top of the tube after one hour. Results are typically compared to the normal range for a person of the same sex and age, although normal range values ​​may vary slightly from laboratory to laboratory.

[0111]

[0054] The term "ferritin" as used herein refers to serum ferritin, which is the ferritin in the blood. Ferritin is a protein that stores iron in cells. Results are typically compared to the normal range for people of the same sex and age, although normal range values ​​may vary slightly from laboratory to laboratory.

[0112]

[0055] "Fever resolution" as used herein means the absence of a temperature >37.5°C for 48 hours.

[0113]

[0056] The term "NSAIDs" refers to "nonsteroidal anti-inflammatory drugs" commonly used to relieve pain and reduce fever. Common NSAIDs include aspirin, ibuprofen, and naproxen sodium. Other NSAIDs include celecoxib, diclofenac, fenoprofen, indomethacin, ketorolac tromethamine, meclofenamate sodium, diflunisal, tolmetin, ketoprofen, and flurbiprofen.

[0114]

[0057] "Modified Pouchot score" refers to a score that can indicate whether a patient has active disease. For each of the following 12 clinical conditions, a score number of 1 is assigned for any condition present at the time of evaluation: fever; transient rash; pharyngitis; arthritis; myalgia; pleurisy; pericarditis; pneumonia; lymphadenopathy; hepatomegaly or elevated liver enzymes; white blood cell count >15,000 / μl; ferritin >3000 μg / l. A total score of >4 is considered to indicate active disease.

[0115] "Systemic-onset juvenile idiopathic arthritis" or "systemic juvenile idiopathic arthritis" or "SoJIA" or "SJIA" or "sJIA" refers to a subset of juvenile idiopathic arthritis characterized by more severe extra-articular symptoms (fever, skin rash). It represents 10-11% of cases of juvenile idiopathic arthritis. Onset usually occurs between 3-5 years of age. Clinical signs include fever with cyclic fluctuations in body temperature and peaks of 39°C or higher over a 24-hour period, which is accompanied by a transient skin rash and generalized lupus erythematosus or urticaria-like lesions. Another symptom is arthritis. The number of body parts affected by arthritis varies, but small and large joints are affected almost symmetrically. Some patients may also have adenopathy and / or hepatosplenomegaly. Other symptoms may be present, such as pericarditis, pleural effusion, or serous peritonitis with abdominal pain. SoJIA patients typically have a severe inflammatory disease in which ferritin levels are greatly increased and the percentage of glycated ferritin is decreased. Physicians often diagnose the disease using the "clinical triad": daily fever lasting more than two weeks, arthritis, and a skin rash. See Petty, R, et al., J. Rheumatol. 31(2) 390-392 (2004). If the patient does not have a skin rash, the presence of adenopathy, hepatosplenomegaly, or serous exudates can also support the diagnosis.

[0116] Anti-IL-18 antibody In some embodiments, the anti-IL-18 antibodies utilized for therapeutic purposes described herein comprise the CDR sequences, and in some embodiments, the antibody 12_GL heavy and light chain variable regions disclosed in WO2012 / 085015, which is incorporated herein by reference in its entirety. Antibody 12_GL is referred to herein as Antibody A. Antibody A is a fully human IgG1κ monoclonal antibody (mAb) that binds to and neutralizes IL-18.

[0117] Antibody A inhibits the formation of IL-18 / Rα / Rβ active complex in vitro and in vivo. Antibody A shows high affinity of 63 pM, 6-fold higher than the natural inhibitor of IL-18 (IL-18 binding protein), and reduced Fc binding, allowing for an efficient anti-inflammatory role. As a fully human antibody, Antibody A is expected to show reduced anti-drug antibodies (ADA). Antibody A has demonstrated L-18 neutralization and bioactivity, reducing the action of IL-18 with sub-nanomolar IC50 in various in vitro models, and has proven efficient in a COPD model (NHBE cells infected with human rhinovirus (HRV) by inhibiting IFN-γ release 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 / week.

[0118]

[0061] In some embodiments, the anti-IL-18 antibody comprises the CDRs of antibody A: (a) HCDR1 having an amino acid sequence identical to or including the amino acid sequence of SEQ ID NO: 122; (b) HCDR2 having an amino acid sequence identical to or including the amino acid sequence of SEQ ID NO: 123; (c) HCDR3 having an amino acid sequence identical to or including the amino acid sequence of SEQ ID NO: 124; (d) LCDR1 having an amino acid sequence identical to or including the amino acid sequence of SEQ ID NO: 126; (e) LCDR2 having an amino acid sequence identical to or including the amino acid sequence of SEQ ID NO: 127; and (f) LCDR3 having an amino acid sequence identical to or including the amino acid sequence of SEQ ID NO: 128.

[0119]

[0062] In some embodiments, the anti-IL-18 antibody comprises an antibody A VH domain (SEQ ID NO: 121) that can be paired with an antibody A VL domain (SEQ ID NO: 125) such that an antibody antigen-binding site is formed that comprises both the antibody A VH and VL domains.

[0120] In some embodiments, an anti-IL-18 antibody is utilized for both 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 subject).

[0121] In some embodiments, anti-IL-18 antibodies useful for therapeutic purposes may comprise the CDR sequences or heavy and light chain variable regions of the antibodies disclosed in WO2012 / 085015, the entirety of which is incorporated herein by reference. The antibodies of WO2012 / 085015 referred to herein include Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Antibody A.

[0122]

[0065] Anti-IL-18 antibodies useful for therapeutic purposes may alternatively contain the CDR sequences of other anti-IL-18 antibodies known in the art (see, e.g., US6706487, WO2001 / 058956, EP1621616, US2005 / 0147610; EP0974600; and WO0158956).

[0123]

[0066] The anti-IL-18 antibody may alternatively comprise any of the CDR sequences or heavy and light chain variable regions of the antibodies disclosed in US8,133,978B2, the entirety of which is incorporated herein by reference. The antibodies of US8,133,978B2 referred to herein include the humanized anti-IL-18 antibodies referred to in claims 1 to 7 of US8,133,978B2. In some embodiments, the anti-IL-18 antibody is GSK1070806. GSK1070806 is a humanized IgG1 / kappa antibody that binds to human IL-18 with high affinity (Kd=30.3 pM) and neutralizes its function. See, e.g., Reid, P. et al., Int J Clin Pharmacol Ther. 2014 Oct;52(10):867-79 doi:10.5414 / CP202087.

[0124] In some embodiments, the anti-IL-18 antibodies of the present invention inhibit the binding of IL-18 to one or both of the IL-18 receptors (IL-18R, including IL-18Rα / IL-18Rβ) and IL-18BP, thereby reducing IL-18 activity. In some embodiments, the anti-IL-18 antibodies may bind to an epitope on the IL-18 molecule that overlaps fully or partially with the IL-18BP binding site.

[0125]

[0068] For example, an anti-IL-18 antibody may specifically bind to an epitope of IL-18 that includes one or more of residues Tyr1, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56, Pro57, Arg58, Gly59, Met60, Arg104, Ser105, and Pro107 of human IL-18, or corresponding residues from IL-18 of other species, e.g., primates such as rhesus monkeys. The anti-IL-18 antibody may bind to an IL-18 epitope that includes 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.

[0126] In some embodiments, the anti-IL-18 antibodies useful in the methods described herein may comprise one or more CDRs described herein, such as CDR3, and optionally also CDR1 and CDR2 to form a set of CDRs. In some embodiments, the CDR or set of CDRs may be any of the CDRs or set of CDRs of antibody 1, antibody 1_GL, antibody 2, antibody 3, antibody 4, antibody 5, antibody 6, antibody 6_GL, antibody 7, antibody 7_GL, antibody 8_GL, antibody 9, antibody 10, antibody 11, antibody 11_GL, and antibody A, or a variant thereof described herein.

[0127] In some embodiments, HCDR1 may be about 7 amino acids long, including or consisting of Kabat residues 31-35b; HCDR2 may be about 16 amino acids long, including or consisting of Kabat residues 50-65; HCDR3 may be about 15 amino acids long, including or consisting of Kabat residues 95-102; LCDR1 may be about 11 amino acids long, including or consisting of Kabat residues 24-34; LCDR2 may be about 7 amino acids long, including or consisting of Kabat residues 50-56; and / or LCDR3 may be about 9 amino acids long, including or consisting of Kabat residues 89-97. As known in the art, in the variable region of the heavy chain, the CDRs may include residues 31-35 plus the insertion of two residues, 35a and 35b.

[0128]

[0071] In some embodiments, the anti-IL-18 antibody comprises HCDR1, HCDR2 and / or HCDR3, and / or LCDR1, LCDR2 and / or LCDR3 shown in Table 6 (CDRs belong to individual antibodies). The anti-IL-18 antibody may comprise a VH set forth in any one of the antibodies in Table 6. Optionally, the anti-IL-18 antibody may also comprise a VL of any one of these antibodies. The VL may be from the same or a different antibody as the VH. 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.

[0129] In some embodiments, the anti-IL-18 antibody is an antibody A having an amino acid residue substitution. CDRs include: (a) an HCDR1 having an amino acid sequence identical to SEQ ID NO: 122 or an amino acid sequence containing 1, 2, or 3 amino acid residue substitutions compared to SEQ ID NO: 122; (b) an HCDR2 having an amino acid sequence identical to SEQ ID NO: 123 or an amino acid sequence containing 1, 2, 3, or 4 amino acid residue substitutions compared to SEQ ID NO: 123; (c) an HCDR3 having an amino acid sequence identical to SEQ ID NO: 124 or an amino acid sequence containing 1, 2, 3, 4, or 5 amino acid residue substitutions compared to SEQ ID NO: 124; (d) an LCDR1 having an amino acid sequence identical to SEQ ID NO: 126 or an amino acid sequence containing 1, 2, 3, or 4 amino acid residue substitutions compared to SEQ ID NO: 126; (e) an LCDR2 having an amino acid sequence identical to SEQ ID NO: 127 or an amino acid sequence containing 1, 2, 3, or 4 amino acid residue substitutions compared to SEQ ID NO: 127; and (f) an LCDR3 having an amino acid sequence identical to SEQ ID NO: 128 or an amino acid sequence containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acid residue substitutions compared to SEQ ID NO: 128.

[0130] In some embodiments, the anti-IL-18 antibody comprises the heavy and / or light chains of the parent antibody. In some embodiments, the anti-IL-18 antibody comprises any of the antibodies listed in Table 6 with one or more substitutions in the CDRs. In some embodiments, the anti-IL-18 antibody comprises any of the antibodies listed in Table 6 with one or more substitutions in the VH and / or VL. For example, the antibody molecule of the present invention can comprise any one of Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Antibody A with 17, 16 or 15 or fewer substitutions in the VH and / or VL, for example, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 substitution. Substitutions may be made in any group, including within the set of CDRs.

[0131] Typically, a VH domain is paired with a VL domain to provide an antibody antigen-binding site, although as described above, either the VH or VL domain may be used alone to bind to an antigen. For example, an antibody A VH domain (SEQ ID NO: 121) may be paired with an antibody A VL domain (SEQ ID NO: 125) to form an antibody antigen-binding site that includes both the antibody A VH and VL domains. Similar embodiments are provided for the VH and VL domains of other antibodies disclosed herein.

[0132] In other embodiments, the antibody A VH is paired with a VL domain other than the VL domain of the antibody A VL. Promiscuity of light chains is well established in the art. Again, similar embodiments for the other VH and VL domains disclosed herein are provided by the present invention. Thus, the VH of parent antibody 1, or any of the optimized clones Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Antibody A may be paired with a VL domain from a different antibody, for example the VH and VL domains may be from a different antibody selected from Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Antibody A.

[0133]

[0076] In some embodiments, the anti-IL-18 antibody comprises a VH domain and a VL domain, (i) wherein 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) wherein 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 compared to SEQ ID NO: 121 and the VL domain amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 amino acid substitutions compared to SEQ ID NO: 125; or (iii) wherein 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 has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 125.

[0134] In some embodiments, the anti-IL-18 antibody comprises a VH domain having an amino acid sequence that is at least 90% identical to the complete sequence of SEQ ID NO: 121. In some embodiments, the anti-IL-18 antibody comprises a VH domain having an amino acid sequence that is at least 90% identical to the complete sequence of SEQ ID NO: 121. In some embodiments, the anti-IL-18 antibody comprises a VL domain having an amino acid sequence that is at least 90% identical to the complete sequence of SEQ ID NO: 125. In some embodiments, the anti-IL-18 antibody comprises a VL domain having an amino acid sequence that is at least 90% identical to the complete 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 complete sequences of SEQ ID NOs: 121 and 125.

[0135]

[0078] In some embodiments, the anti-IL-18 antibody comprises a heavy chain and a light chain comprising the following complementarity determining regions (CDRs): (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 129; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 130; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 131; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 132; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 133; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 134.

[0136] In some embodiments, the anti-IL-18 antibodies of the present invention comprise a heavy chain and a light chain that comprise the following complementarity determining regions (CDRs): (a) an HCDR1 having an amino acid sequence identical to SEQ ID NO: 129, or an amino acid sequence that contains 1, 2, or 3 amino acid residue substitutions compared to SEQ ID NO: 129; (b) an HCDR2 having an amino acid sequence identical to SEQ ID NO: 130, or an amino acid sequence that contains 1, 2, 3, or 4 amino acid residue substitutions compared to SEQ ID NO: 130; (c) an HCDR3 having an amino acid sequence identical to SEQ ID NO: 131, or an amino acid sequence that contains 1, 2, 3, 4, or 5 amino acid residue substitutions compared to SEQ ID NO: 131. (d) an LCDR1 having an amino acid sequence identical to SEQ ID NO: 132 or an amino acid sequence that contains 1, 2, 3 or 4 amino acid residue substitutions compared to SEQ ID NO: 132; (e) an LCDR2 having an amino acid sequence identical to SEQ ID NO: 133 or an amino acid sequence that contains 1, 2, 3 or 4 amino acid residue substitutions compared to SEQ ID NO: 133; and (f) an LCDR3 having an amino acid sequence identical to SEQ ID NO: 134 or an amino acid sequence that contains 1, 2, 3 or 4 amino acid residue substitutions compared to SEQ ID NO: 134.

[0137] In some embodiments, the IL-18 antibody comprises a heavy chain having an amino acid sequence identical to, or including 1-12 amino acid residue substitutions compared to, a heavy chain selected from the group consisting of SEQ ID NO:137, SEQ ID NO:145, and SEQ ID NO:149, and a light chain having an amino acid sequence identical to, or including 1-12 amino acid residue substitutions compared to, a light chain selected from the group consisting of SEQ ID NO:141 and SEQ ID NO:157. In some embodiments, the anti-IL-18 antibody further comprises replacing the residue at position 71 of the light chain with the corresponding residue found in the donor antibody from which the CDR is 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.

[0138] In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 153. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 153. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO:149 and a light chain of SEQ ID NO:153.

[0139]

[0082] In some embodiments, the anti-IL-18 antibody may lack the antibody constant region, eg, an scFv.

[0140] In other embodiments, the anti-IL-18 antibody may comprise an antibody constant region. The anti-IL-18 antibody may be a whole antibody, such as an IgG (i.e., IgG1, IgG2, or IgG4), or may be an antibody fragment or derivative, as described below. The antibody molecule may also have other formats, such as an IgG1 with YTE (Dall'Acqua et al. (2002) J. Immunology, 169:5171-5180; Dall'Acqua et al. (2006) J Biol. Chem. 281(33):23514-24) and / or TM mutations (Oganesyan et al. (2008) Acta Cryst D64:700-4) in the Fc region.

[0141]

[0084] Another aspect of the present invention provides an anti-IL-18 antibody comprising an antibody antigen-binding site or antibody molecule described herein that (i) binds to IL-18 and (ii) competes for binding to IL-18 with any antibody molecule comprising an antibody molecule listed in Table 6, a VH and / or VL domain, a CDR, e.g., HCDR3, and / or a set of CDRs.

[0142]

[0085] For example, in some embodiments, an anti-IL-18 antibody may compete with an antibody molecule comprising: (i) a VH domain having the sequence of SEQ ID NO: 152 and a VL domain having the sequence of SEQ ID NO: 157; (ii) a VH domain having a sequence which contains 15 or fewer amino acid substitutions, such as 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1, compared to SEQ ID NO: 152; and a VL domain having a sequence which contains 13 or fewer amino acid substitutions, such as 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1, compared to SEQ ID NO: 157, or (iii) a VH domain and a VL domain having sequences which have at least 90% sequence identity to SEQ ID NO: 152 and SEQ ID NO: 157, respectively.

[0143] Competition between anti-IL-18 antibodies can be readily assayed in vitro, for example, using ELISA and / or by biochemical competition assays, for example, tagging one anti-IL-18 antibody with a specific reporter molecule that can be detected in the presence of one or more other untagged anti-IL-18 antibodies, allowing the identification of anti-IL-18 antibodies that bind to the same or overlapping epitopes. Such methods are readily known to those skilled in the art and are described in more detail herein.

[0144]

[0087] Variable domain amino acid sequence variants of any of the VH and VL domains whose sequences are specifically disclosed herein may be used in accordance with the present invention.

[0145]

[0088] As described above, aspects of the present invention provide anti-IL-18 antibodies comprising a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with the VH domain of any of the antibodies listed herein, wherein the VH domain sequence is set out in the attached Table 6 below; and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with the VL domain of any of the antibodies listed herein, wherein the VL domain sequence is set out in the attached Table 6 below.

[0146]

[0089] Aspects of the present invention provide anti-IL-18 antibodies comprising a VH domain having a set of VH CDRs which have at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with the set of VH CDRs of any of the antibodies listed herein, wherein the VH CDR sequences are set out in the attached Table 6; and / or a VL domain having a set of VL CDRs which have at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with the set of VL CDRs of any of the antibodies listed herein, wherein the VL CDR sequences are set out in the attached Table 6.

[0147]

[0090] 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], for example, using default parameters.

[0148] Pharmaceutical preparations

[0091] Anti-IL-18 antibodies can be administered in the form of a pharma- ceutically acceptable composition. In various embodiments, compositions comprising anti-IL-18 antibodies are provided in formulations containing a wide variety of pharma- ceutically acceptable carriers (see, for example, 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)). A variety of pharma- ceutically acceptable carriers, including solvents, adjuvants, and diluents, are available. In addition, a variety of pharma- ceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, isotonicity agents, stabilizers, wetting agents, and the like, are also available. Non-limiting exemplary carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.

[0149] In various embodiments, compositions comprising anti-IL-18 antibodies can be formulated for injection or infusion by dissolving, suspending, or emulsifying in aqueous or non-aqueous solvents, such as vegetable or other oils, synthetic fatty acid glycerides, esters of higher fatty acids, or polyethylene glycols, and, if desired, with conventional additives, such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives. In various embodiments, the compositions can be formulated for inhalation, for example, using pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. The compositions can also be formulated in various embodiments, for example, with biodegradable or non-biodegradable polymers into sustained release microcapsules. Non-limiting exemplary biodegradable formulations include polylactic acid-glycolic acid polymers. Non-limiting exemplary non-biodegradable formulations include polyglycerol fatty acid esters. Certain methods of making such formulations are described, for example, in EP1125584A1.

[0150] Pharmaceutical packs and kits are also provided that include one or more containers, each container containing one or more doses of an anti-IL-18 antibody. In some embodiments, unit dosage forms are provided that contain a predetermined amount of a composition that includes an anti-IL-18 antibody with or without one or more additional agents. In some embodiments, such unit dosage forms are supplied in a single-use pre-filled syringe for injection. In various embodiments, the composition contained in the unit dosage form may include saline, sucrose, etc.; a buffer, such as a phosphate buffer, 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, the composition of the present invention includes heparin and / or proteoglycan.

[0151] Treatment with anti-IL-18 antibodies

[0094] In some embodiments, a method for treating a subject having AOSD or SoJIA is provided, the method comprising administering an effective amount of an anti-IL-18 antibody to a human subject diagnosed with Adult-onset Still's disease (AOSD) or systemic-onset juvenile idiopathic arthritis (SoJIA).

[0152]

[0095] In some embodiments, a subject is diagnosed with AOSD based on having five or more of the following criteria, two of which are major criteria: (a) Major criteria Fever >39°C for more than 1 week Joint pain or arthritis lasting more than 2 weeks Typical rash >10,000 mm of white blood cells with >80% polymorphonuclear cells 3 (b) Minor criteria sore throat Recent onset of significant lymphadenopathy Hepatomegaly or splenomegaly Abnormal liver function tests Tests for antinuclear antibody (IF) and rheumatoid factor (IgM) were negative.

[0153]

[0096] In some embodiments, the subject reports a recurrence of fever >38°C within the last 5 days of the Screening and Baseline visit.

[0154] In some embodiments, if the subject is being treated with NSAIDs, the subject has been on a stable dose for at least 48 hours prior to the baseline visit. In some embodiments, if the subject is being treated with glucocorticoids, the subject has been on a stable dose for at least 48 hours prior to the baseline visit. In some embodiments, if the subject is being treated with conventional DMARDs, the subject has been on a stable dose for at least 12 weeks prior to the baseline visit. In some embodiments, if the subject is being treated with biologic DMARDs, the subject has undergone a required off-drug period prior to the baseline visit, the required off-drug periods being as follows: anakinra - 1 week; etanercept, rilonacept - 4 weeks; adalimumab, certolizumab, infliximab, golimumab, abatacept, tocilizumab, and canakinumab - 8 weeks; and rituximab - 36 weeks.

[0155] In some embodiments, the subject does not have a serum creatinine concentration >1.5 mg / dl. In some embodiments, the subject does not have hemoglobin < 10 g / dl, neutrophils < 1,500 / μl, and / or platelets < 75,000 / μl.

[0156]

[0099] In some embodiments, the methods include methods of treating SoJIA.

[0157] In some embodiments, the subject has elevated free or total serum IL-18 levels. In some embodiments, the level of serum IL-18 is measured before administration of an anti-IL-18 antibody. In some embodiments, the level of serum IL-18 is measured after administration of an anti-IL-18 antibody. In some embodiments, the level of serum IL-18 is measured as a marker of efficacy of treatment. In some embodiments, the level of serum IL-18 is elevated compared to levels in subjects without AOSD or SoJIA or compared to a negative control. In some embodiments, the level of serum IL-18 in the subject is measured after administration of an anti-IL-18 antibody as a marker of efficacy of treatment. In some embodiments, the level of serum IL-18 is free IL-18. In some embodiments, the level of free IL-18 is calculated. In some embodiments, the level of serum IL-18 is total IL-18. In some embodiments, the subject has elevated serum free IL-18. In some embodiments, the subject has elevated serum total IL-18.

[0158]

[0101] In some embodiments, the anti-IL-18 antibody is administered in the form of a pharma- ceutically acceptable composition.

[0159] In some embodiments, the anti-IL-18 antibody is administered for at least 16 weeks. In some embodiments, the anti-IL-18 antibody is administered intravenously. In some embodiments, the anti-IL-18 antibody is administered subcutaneously.

[0160]

[0103] In some embodiments, 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.

[0161]

[0104] In some embodiments, the subject achieves resolution of fever.

[0162] In some embodiments, the subject achieves a reduction in CRP. In some embodiments, the subject achieves a ≧50% reduction in CRP from baseline by week 4. In some embodiments, the subject achieves a ≧50% reduction in CRP from baseline by week 12.

[0163] In some embodiments, the subject achieves a reduction in serum IL-18 levels. In some embodiments, the subject achieves a reduction in serum total IL-18 levels. In some embodiments, the subject achieves a reduction in serum free IL-18 levels. In some embodiments, the subject has an undetectable level of serum IL-18 at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has an undetectable level of serum IL-18 at about 12 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has an undetectable level of serum total IL-18 at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has an undetectable level of serum total IL-18 at about 12 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has an undetectable level of serum free IL-18 at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has an undetectable level of serum free IL-18 at about 12 weeks after administration of the anti-IL-18 antibody.

[0164] In some embodiments, the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by a physician and / or patient global assessment of disease activity as assessed by a visual analog scale (VAS). In some embodiments, the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by a physician and / or patient global assessment of disease activity as assessed by a visual analog scale (VAS) at least about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by a physician and / or patient global assessment of disease activity as assessed by a visual analog scale (VAS) at least about 12 weeks after administration of the anti-IL-18 antibody.

[0165] In some embodiments, the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a modified Pouchot score. In some embodiments, the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a modified Pouchot score at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a modified Pouchot score at about 12 weeks after administration of the anti-IL-18 antibody.

[0166] In some embodiments, the subject shows a reduction in signs and symptoms of AOSD or SoJIA as assessed using the DAS28-CRP score. In some embodiments, the subject shows a reduction in signs and symptoms of AOSD or SoJIA as assessed using the DAS28-CRP score at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject shows a reduction in signs and symptoms of AOSD or SoJIA as assessed using the DAS28-CRP score at about 12 weeks after administration of the anti-IL-18 antibody.

[0167] In some embodiments, the subject experiences a decrease in serum ferritin. In some embodiments, the subject experiences a decrease in serum ferritin at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject experiences a decrease in serum ferritin at about 12 weeks after administration of the anti-IL-18 antibody.

[0168] In some embodiments, the subject experiences a decrease in erythrocyte sedimentation rate (ESR). In some embodiments, the subject experiences a decrease in erythrocyte sedimentation rate (ESR) at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject experiences a decrease in erythrocyte sedimentation rate (ESR) at about 12 weeks after administration of the anti-IL-18 antibody.

[0169]

[0112] In some embodiments, the subject is administered one or more additional therapeutically active agents. In some embodiments, the one or more additional therapeutically active agents include at least one of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, systemic glucocorticoids, and conventional systemic disease-modifying antirheumatic drugs (DMARDs). In some embodiments, the conventional systemic disease-modifying antirheumatic drug (DMARD) is methotrexate. In some embodiments, the corticosteroid is prednisone.

[0170] Free IL-18 detection assay Most currently available assays only measure total IL-18, including IL-18 bound to its receptor, including IL-18bp. Total IL-18 may not provide a sufficiently accurate picture of the level of disease-causing IL-18, which may be free unbound IL-18. Therefore, when a method includes the detection of free IL-18, it may be desirable to use an assay that measures only free IL-18. Alternatively, free IL-18 can be calculated based on total IL-18 and total IL-18bp concentration data using formulas known in the art.

[0171] Kits and Products Any of the foregoing methods can be performed with a kit for detection and / or treatment of conditions associated with elevated IL-18, including AOSD or SoJIA. The kit may contain an antibody, one or more non-naturally occurring detectable labels, markers, or reporters, a pharma- ceutically acceptable carrier, a physiologically acceptable carrier, instructions for use, a container, a container for administration, an assay substrate, or any combination thereof.

[0172]

[0115] In some embodiments, the kit is for use in a method of detecting IL-18 in a biological sample. The kit may contain an anti-IL-18 antibody and reagents for carrying out the method.

[0173] In some embodiments, the kit is for use in a method for detecting IL-18 in a biological sample from a subject having or suspected of having AOSD or SoJIA. The kit may contain an anti-IL-18 antibody and reagents for carrying out the method.

[0174] In some embodiments, the kit is for use in a method of detecting elevated IL-18 in a biological sample from a subject, optionally where the subject is suspected of having AOSD or SoJIA, and also for treating the subject following diagnosis by administering an effective amount of an anti-IL-18 antibody. The kit may contain an anti-IL-18 antibody and reagents for carrying out the method.

[0175] In some embodiments, the kits for use in the methods of detection and / or treatment include a solid phase to which the anti-IL-18 antibody or reagent binds. In some embodiments, the kits for use in the methods of detection and / or treatment include a solid phase to which IL-18 from a biological sample will bind.

[0176]

[0119] The solid phases used in the kits of the present invention include, but are not limited to, microplates, magnetic particles, immunochromatographic filters, polymers such as polystyrene, glass beads, glass filters, and other insoluble carriers. In one embodiment, a solid substrate containing many compartments or regions has at least one compartment coated with an antibody of the present invention.

[0177] The kit of the present invention may also include additional components to the diagnostic agent, anti-IL-18 antibody, including, but not limited to, reagents, enzymes for labeling and substrates therefor, radioisotopes, light-reflecting substances, fluorescent substances, coloring substances, buffers, and plates, as well as those mentioned herein above. EXAMPLES

[0178] The following examples are presented to illustrate certain disclosed embodiments and should not be construed as limiting the scope of the disclosure. In the examples disclosed below, "Antibody A" refers to an anti-IL-18 antibody that comprises the following six CDRs: a heavy chain CDR having the amino acid sequence of SEQ ID NO: 122; a heavy chain CDR having the amino acid sequence of SEQ ID NO: 123; a heavy chain CDR having the amino acid sequence of SEQ ID NO: 124; a light chain CDR having the amino acid sequence of SEQ ID NO: 126; a light chain CDR having the amino acid sequence of SEQ ID NO: 127; and a light chain CDR having the amino acid sequence of SEQ ID NO: 128. In some embodiments, Antibody A has a variable heavy chain (VH) having the amino acid sequence of SEQ ID NO: 121 and a variable light chain (VL) having the amino acid sequence of SEQ ID NO: 125. EXAMPLES

[0179] Example 1 - A Phase 1b, Multicenter, Open-Label Study Evaluating the Safety and Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Antibody A in Subjects with Adult-Onset Still's Disease Example 1.1 - Study Objectives and Endpoints The primary objective of the study is to evaluate the safety and tolerability of antibody A at a dose of 7 mg / kg (maximum 500 mg) in subjects with AOSD. This is the first time that antibody A has been tested in subjects with AOSD. Initially, six subjects were enrolled at the 7 mg / kg dose. If this dose was found by the safety review committee to be tolerable in the first six subjects, the dose was increased to 14 mg / kg (maximum 1000 mg) in the next set of six subjects. Before proceeding with dose escalation in the second cohort of subjects, the safety review committee had the option to decide to expand the number of subjects in the first cohort by a predefined algorithm. If the safety of antibody A at the 7 mg / kg dose was not acceptable, the dosing was reduced to a dose of 4 mg / kg (maximum 300 mg) by a predefined algorithm.

[0180]

[0123] Secondary objectives of the study are to evaluate the effect of Antibody A on systemic clinical signs of AOSD; to measure the effect of Antibody A on systemic inflammatory markers in subjects with AOSD; and to evaluate the PK of Antibody A in subjects with AOSD.

[0181]

[0124] Exploratory objectives are to evaluate the PD of Antibody A in subjects with AOSD and to evaluate the immunogenicity of Antibody A in subjects with AOSD.

[0182]

[0125] The primary endpoints of the study were the occurrence of AEs, and changes in vital signs and clinical laboratory results.

[0183]

[0126] Secondary endpoints of the study were the proportion of subjects who achieved fever resolution, defined as the absence of a temperature >37.5°C for 48 hours; the proportion of subjects who achieved a >50% decrease in CRP from baseline to weeks 4 and 12; change from baseline to weeks 4 and 12 in physician and patient global assessment of disease activity, assessed on a VAS ranging from no evidence of disease (0mm) to very severe disease activity (100mm); change from baseline to weeks 4 and 12 in modified Pouchot score; change from baseline to weeks 4 and 12 in DAS28-CRP; change from baseline to weeks 4 and 12 in CRP, ferritin, and ESR; and serum concentrations of Antibody A over time.

[0184]

[0127] The exploratory endpoints of the study are the change from baseline in IL-18 and IL-18BP levels, and the occurrence of ADA against antibody A. IL-18 is considered an efficient marker for the diagnosis and follow-up of AOSD (Jung et al. (2014) Scand J Rheumatol. 43(2):162-169).

[0185] Example 1.2 - Study Design

[0128] The trials will be conducted at approximately 15 testing facilities in the United States and Europe.

[0186] Approximately 12 subjects aged 18-75 years with AOSD will be enrolled. This age range has been selected considering that AOSD is seen in adults and subjects over 65 years of age. The diagnosis of AOSD was based on the classification criteria by Yamaguchi et al. (1992) J Rheumatol. 19(3):424-430, which is the most sensitive classification criteria (Fong and Lui (2013) Proceedings of Singapore Healthcare. 22(1):40-47).

[0187] Selection Criteria

[0130] Subjects must meet the following study eligibility requirements: 2. Subjects are aged 18-75 years at the time of consent (enrollment). The date of signing the informed consent form defines the start of the screening period. This inclusion criterion will be assessed only at the screening visit (Visit 1). 3. Subjects have been diagnosed with AOSD based on classification criteria (Yamaguchi et al. (1992) J Rheumatol. 19(3):424-430) defined as having 5 or more of the following criteria, two of which are major criteria: a. Major criteria i. Fever >39°C for more than one week ii. Joint pain or arthritis lasting for more than 2 weeks iii. Typical rash iv. >10,000 mm of white blood cells with >80% polymorphonuclear cells 3 b. Minor criteria i. Sore throat ii. Recent onset of significant lymphadenopathy iii. Hepatomegaly or splenomegaly iv. Abnormal liver function tests v. Antinuclear antibody (IF) and rheumatoid factor (IgM) tests negative 4. Subject reports recurrent fever >38°C consistent with active disease within the last 5 days following the Screening and Baseline visits. 5. If being treated with NSAIDs, subjects must have been receiving a stable dose for at least 48 hours prior to the Baseline visit (Visit 2). 6. If receiving glucocorticoid treatment, subjects must have been receiving a stable dose for at least 48 hours prior to the Baseline visit (Visit 2). 7. If being treated with conventional DMARDs, subjects must have been on a stable dose for at least 12 weeks prior to the Baseline visit (Visit 2). 8. For subjects receiving treatment with a biologic DMARD, subjects will have a required washout (normalization) period prior to the Baseline visit (Visit 2). The washout (normalization) periods for biologic DMARDs are as follows: a. Anakinra - 1 week b. Etanercept, Rilonacept - 4 weeks c. Adalimumab, certolizumab, infliximab, golimumab, abatacept, tocilizumab, and canakinumab - 8 weeks d. Rituximab - 36 weeks 9. Women of childbearing potential and men with female partners of childbearing potential participating in the study agree to use highly effective contraception throughout the study and for 28 days after the last dose of study drug. Highly effective contraception is defined as a method that, when used consistently and correctly, results in a low failure rate (i.e., <1% per year), such as oral / injectable / insertive / implantable / transdermal contraceptives, condom-diaphragm combination, condom-spermicide combination, diaphragm-spermicide combination, intrauterine hormone-releasing system or intrauterine device (IUD), or abstinence. Contraception is not required if at least 6 weeks have passed since sterilization, defined as hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy, and men who have had a vasectomy. Contraception is not required if women are postmenopausal (physiological amenorrhea for 12 consecutive months and age ≥ 51 years). 10. Subjects have provided written informed consent for this study. 11.The subject is willing and able to comply with the study protocol.

[0188] Exclusion criteria The presence of any of the following criteria will exclude a subject from the study: 1. In the opinion of the Investigator, the subject is mentally or legally incapacitated or has significant emotional problems at the time of the Screening Visit (Visit 1) that may prevent the subject from participating or cooperating in the performance of study evaluations. 2. The subject has a chronic severe or uncontrolled medical disorder that may confound the results of the safety evaluations conducted in the study. 3. Subject has another severe chronic inflammatory disease. 4. Subject has an associated active infection or another disease with infectious tendencies. 5. The subject has active Macrophage Activation Syndrome. 6. Subject has a history of unresolved latent tuberculosis. 7. The subject has the following abnormalities: Serum creatinine concentration >1.5 mg / dl. b. Hemoglobin ≤ 10 g / dl, neutrophils ≤ 1,500 / μl, and / or platelets ≤ 75,000 / μl. 8. Subject has a history of tumor, except for curatively treated non-melanoma skin tumors or in situ treated cervical cancer, within the past 10 years with no signs of recurrence. 9. Subject has been vaccinated with a live vaccine within 12 weeks prior to the Baseline visit (Visit 2). 10. Subject has used an investigational drug or is enrolled in a clinical trial involving a vaccine within 30 days of the screening visit (Visit 1). 11. Subject has known or suspected intolerance or hypersensitivity to the investigational drug, closely related compounds, or any component of the investigational drug.

[0189] Screening dropout

[0132] Subjects who drop out due to inclusion and / or exclusion criteria may be rescreened for the study with prior approval of the Medical Monitor. In the case of rescreening, the initial 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 unscheduled visits.

[0190] Early Discontinuation by Subject

[0133] All subjects will be informed that they are free to discontinue participation in the study at any time, for any reason, and without repercussion. Every effort should be made by the investigator to retain the subject in the study, but if the subject withdraws consent to participate, the study must be discontinued. The investigator should attempt to contact by telephone or other means any subject who misses a scheduled visit to exclude the possibility that an AE is the cause of discontinuation. If this is the case, the AE should be documented, reported, and followed up.

[0191]

[0134] Subjects may refuse to continue receiving study drug at any time during the study, in which case the Investigator will discuss with the subject completing a follow-up / early termination visit 4 weeks after the last dose of study drug.

[0192]

[0135] Withdrawal of consent from a study means that the subject does not wish to receive any further treatment or procedures specified in the study protocol and that the subject is unwilling or unable to continue further study participation. Subject data up until withdrawal of consent will be included in the study analysis, and publicly available data may be included after withdrawal of consent, if permitted. If withdrawal of consent occurs before 4 weeks have elapsed since the last dose of study drug, the investigator shall discuss with the subject the procedure for a "safety follow-up call" that will occur 4 weeks after the last dose of study drug. The subject may refuse to participate in the call.

[0193]

[0136] The Sponsor reserves the right to request deviations from the protocol or withdrawal of a subject for other reasons.

[0194]

[0137] The investigator also has the right to discontinue a subject from the study at any time for any reason. If a subject discontinues before completion of the study, the subject should be followed up as directed in the assessment schedule (Table 1). The reason for discontinuation will be determined by the investigator and must be recorded in the subject's medical record and electronic case report form (eCRF). If a subject discontinues for more than one reason, each reason should be documented in the source document, and the most clinically relevant reason should be entered into the eCRF.

[0195] Reasons for discontinuation include, but are not limited to, the following: Lack of efficacy, including worsening of symptoms, disease progression, or lack of improvement Adverse Events ·death -Non-compliance with study procedures / protocol Investigator discretion At Sponsor's discretion Withdrawal of consent by subject Untraceable Other (specify). For example, pregnancy.

[0196] Subject replacement criteria

[0139] Subjects who discontinue the study for reasons other than drug toxicity may be replaced with prior approval of the Medical Monitor.

[0197] [Table 1-1]

[0198] [Table 1-2]

[0199] [Table 1-3]

[0200] [Table 1-4]

[0201] Example 1.3 - Treatment Identification of the study drug, dose, and method of administration Antibody A is the investigational drug used and has been used in this study. Antibody A was in the form of a lyophilized powder in single-use glass vials. The dose was 7 mg / kg (maximum 500 mg) for the first cohort of six subjects. A predefined algorithm will determine the dosing for the second cohort of six subjects. The frequency of dosing was and is once every four weeks during the treatment period. The method of administration was and is intravenous.

[0202] Treatment administered Antibody A will and has been administered IV to a first cohort of six subjects at a dose of 7 mg / kg (maximum 500 mg) once every four weeks. Safety will and has been assessed by the SRC for these six subjects. 28 days after the sixth subject in the first cohort completes the first dose of antibody A, if safety is acceptable per a predefined algorithm, a second cohort of six subjects will receive 14 mg / kg IV (maximum 1000 mg). Per a predefined algorithm, the SRC may decide to expand the number of subjects in the first cohort before proceeding with dose escalation in the second cohort of subjects. If safety at 7 mg / kg is unacceptable, dosing will be reduced to 4 mg / kg (maximum 300 mg) per a predefined algorithm.

[0203] To reduce the risk of infusion reactions, Antibody A will and has always been administered by slow IV infusion (over a minimum of 60 minutes). Appropriate medications and medical equipment to treat acute anaphylaxis must be immediately available, and study personnel must be trained to recognize and treat anaphylaxis. Subjects should be observed for signs and symptoms of hypersensitivity or allergic reactions, with vital signs monitored as needed, from administration of Antibody A until PK sampling 2 hours post-dose.

[0204] Blinded and unblinded treatment allocation

[0143] This is an open-label study.

[0205] Dose Selection for the Study

[0144] Doses of 4, 7, and 14 mg / kg administered once every 4 weeks were contemplated or used in this study.

[0206] Dose adjustment criteria Antibody A will and has been administered IV to a first cohort of six subjects at a dose of 7 mg / kg (maximum 500 mg) once every four weeks. If safety is acceptable per a predefined algorithm, based on review by the Safety Review Committee, a second cohort of six subjects will receive 14 mg / kg IV (maximum 1000 mg). Per a predefined algorithm, the SRC may decide to expand the number of subjects in the first cohort before proceeding with dose escalation in the second cohort of subjects. If not acceptable, dosing will be reduced to 4 mg / kg (maximum 300 mg) per a predefined algorithm.

[0207] Pretreatment

[0146] Prior treatment includes any treatment received within 28 days of the first dose of study drug.

[0208] Additionally, all AOSD treatments received at any time during or prior to the 28-day window period described above should be entered with information from the last treatment exposure. For example, a biologic DMARD that was normalized (off for 8 weeks) prior to the baseline visit (Week 0) should have the last date and dose received entered on the appropriate eCRF page.

[0209] Combination treatment

[0148] Concomitant treatment refers to all treatments received from screening through 4 weeks after the last dose of study drug or last visit (whichever is later). Concomitant treatment information must be recorded on the appropriate eCRF page.

[0210]

[0149] Subjects entering the study on a stable dose of glucocorticoids are expected to maintain that dose for the duration of the study. If a change to a lower dose is necessary, this should be made under best medical practice after the Week 4 visit / 28 ​​days while taking study drug.

[0211] Acceptable Treatment

[0150] Patients will be treated for all coexisting medical conditions at the discretion of the investigator according to local medical standards. Subjects will receive treatment to alleviate symptoms associated with AOSD.

[0212]

[0151] Vaccination status of subjects should be reviewed according to current vaccination guidelines prior to study initiation. It is recommended that vaccinations be avoided within 4 weeks of initiating treatment with Antibody A.

[0213] Prohibited Treatments

[0152] If subjects are receiving treatment with NSAIDs and / or glucocorticoids, subjects must meet the 48-hour stable dose requirement prior to the Baseline visit (Visit 2).

[0214]

[0153] Subjects must complete the required normalization (drug-free) period of biologic DMARDs prior to the Baseline Visit (Visit 2). DMARD normalization periods are as follows: a) anakinra (1 week); b) etanercept, rilonacept (4 weeks); c) adalimumab, certolizumab, infliximab, golimumab, abatacept, tocilizumab, and canakinumab (8 weeks); and d) rituximab (36 weeks).

[0215]

[0154] Any new therapy other than Antibody A designed to treat the subject's AOSD is prohibited for the duration of the study. This includes biologics (e.g., anti-IL-1, anti-IL-6, anti-TNFα), and the initiation or increase of any glucocorticoid therapy.

[0216]

[0155] During the study, new initiation of test compounds is prohibited. Vaccines considered by the Investigator during the study should be discussed with the Medical Monitor prior to administration.

[0217]

[0156] Subjects receiving excluded treatments during the study may be ineligible to continue in the study at the sponsor's discretion.

[0218] Treatment after the end of the study

[0157] After discontinuation from the study, subjects may receive treatment at the discretion of the investigator.

[0219] Example 1.4 - Test Procedure Trial duration

[0158] The sequence and maximum duration of the study periods will be as follows: The screening period will be a maximum of 28 days. The treatment period will be 8 weeks. The follow-up period will be 4 weeks after the last dose of study drug or the last visit (whichever is later). The maximum study duration for each subject will be a maximum of 16 weeks. The maximum treatment duration for each subject will be 8 weeks.

[0220] Safety assessment

[0159] Safety and tolerability assessments will include evaluation of the frequency and severity of AEs, as well as changes in clinical laboratory values ​​and vital signs.

[0221] Laboratory tests to be performed

[0160] Samples for the following clinical tests will be collected at the times specified in the evaluation schedule (Table 1).

[0222]

[0161] Hematology tests include hemoglobin, hematocrit, platelet count (or estimated), and white blood cell count including differential count.

[0223]

[0162] Serum chemistry panels include albumin, total bilirubin, total protein, calcium, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, blood urea nitrogen / urea, creatinine, magnesium, glucose, sodium, potassium, chloride, bicarbonate, phosphorous, and uric acid.

[0224]

[0163] Serum / urine pregnancy tests are performed on women of childbearing potential.

[0225]

[0164] Urine testing includes dipstick determination of pH, specific gravity, protein, blood, glucose, and ketones; and microscopy if blood or protein 2+ or greater.

[0226]

[0165] Laboratory specimens are collected and transported to a central laboratory for processing by the appropriate laboratory. Although laboratory results from each site (creatinine, hemoglobin, neutrophils, platelets, and serum pregnancy) may be used to facilitate enrollment, central laboratory specimens must also be collected as part of the screening procedure.

[0227] Amount of blood collected

[0166] The amount of blood collected is shown in Table 2.

[0228] [Table 2]

[0229] Laboratory evaluation

[0167] Normal ranges of test values ​​in this study will be provided by the relevant testing laboratory and are considered reference ranges for the purposes of determination by that particular laboratory.

[0230]

[0168] When a laboratory value is outside the reference range, the laboratory value is not necessarily clinically relevant. The investigator must evaluate the out-of-range value and record an assessment of clinical significance in the subject's source documents. An abnormal laboratory value may be considered an AE if it is clinically significant, requires intervention, or alters the administration of study drug.

[0231]

[0169] Any laboratory test values ​​that, in the opinion of the investigator, indicate clinically relevant or pathologic changes during or after the end of treatment will be discussed with the medical monitor, as appropriate, and reported and tracked as AEs.

[0232] Clinical Assessment: Vital Signs

[0170] Blood pressure, pulse rate, respiratory rate, temperature, and weight will be measured at the time points specified in the assessment schedule (Table 1). If determined by the investigator, additional blood pressure and pulse rate measurements may be taken to ensure adequate monitoring of subject safety and accurate recording of vital sign measurements. Any changes from baseline deemed clinically significant by the investigator will be recorded and tracked as an AE.

[0233] Clinical evaluation: Electrocardiogram

[0171] A standard 12-lead ECG will be performed after the subject has been in the supine position for approximately 5 minutes. All ECG recordings will be identified by subject number, date, and time of recording, and copies will be included with the subject's source documentation.

[0234]

[0172] A 12-lead ECG will be performed at baseline and then at the site as needed (Table 1). Any ECG values ​​that, in the opinion of the investigator, indicate clinically relevant or pathological changes during or after the end of treatment will be discussed with the medical monitor and reported and tracked as an AE.

[0235] Clinical evaluation: Physical examination

[0173] Physical examinations will be performed at the screening visit prior to potential exposure to study drug and at subsequent study visits (Table 1). Any clinically significant physical examination findings after screening will be reported and tracked as an AE.

[0236] Clinical evaluation: Adverse events

[0174] The Investigator is responsible for detecting and documenting events that meet the criteria and definitions of AEs or SAEs described above. At each visit, subjects will be allowed the opportunity to spontaneously report any problems since their last visit or evaluation.

[0237]

[0175] Any clinically relevant observation made during a visit will be considered an AE.

[0238] Effectiveness

[0176] The efficacy of Antibody A will be determined by physician and patient global assessment using fever reduction, CRP, ferritin, ESR, VAS, modified Pouchot score, and DAS28 CRP.

[0239]

[0177] Resolution of fever will be determined by measuring temperature at study visits and collecting subject reports of fever experienced within the last 5 days prior to screening and baseline visits, and within the last 48 hours at any subsequent visits.

[0240]

[0178] Temperature, CRP, ferritin, and ESR will be measured at the times specified in the assessment schedule (Table 1).

[0241]

[0179] Patient Global Assessment of Disease Activity (PtGA) will be measured at the time points specified in the assessment schedule (Table 1) using a 100mm VAS ranging from no evidence of disease (0mm) to very severe disease activity (100mm).

[0242]

[0180] Physician Global Assessment of Disease Activity (PhGA) will be measured at the time points specified in the assessment schedule (Table 1) using a 100mm VAS ranging from no evidence of disease (0mm) to very severe disease activity (100mm). To increase objectivity, physicians should not be aware of the specific PtGA when making their assessment of the patient.

[0243]

[0181] The modified Pouchot score is measured at the time points specified in the assessment schedule (Table 1). For each of the 12 clinical conditions listed, a score number of 1 is assigned for any clinical condition present at the time of assessment (Rau et al. (2010) J Rheumatol. 37(11):2369-2376): fever; transient rash; pharyngitis; arthritis; myalgia; pleurisy; pericarditis; pneumonia; lymphadenopathy; hepatomegaly or elevated liver enzymes; white blood cell count >15,000 / μl; ferritin >3000 μg / l. A total score of >4 is considered to indicate active disease.

[0244]

[0182] DAS28-CRP is measured at the time points specified in the assessment schedule (Table 1). To calculate DAS28-CRP, information on the following disease variables is collected: number of swollen and tender joints using the 28 joint count (TJC28 and SJC28); PtGA measured on a 100 mm VAS; and CRP measured in mg / L.

[0245] Using this data, DAS28-CRP is calculated using the following formula:

[0246]

number

[0247]

[0184] Swollen joints, tender joints and PtGA assessments will be collected and CRP will be used to determine the DAS28-CRP score.

[0248]

[0185] DAS28 scores range from 0 to 10, with higher scores indicating more severe current disease activity. DAS28 scores are also classified into disease activity states according to the cutoff values ​​shown in Table 3.

[0249] [Table 3]

[0250] Pharmacokinetics

[0186] Blood collection for PK analysis will be performed according to Table 1. Serum samples will be analyzed by a validated method for serum Antibody A concentration.

[0251] Pharmacodynamics

[0187] PD is measured by levels of IL-18 and IL-18BP obtained at various time points during study participation (Table 1).

[0252] immunogenicity

[0188] Blood collection for immunogenicity analysis will be performed according to Table 1. Details of immunogenicity sample collection and processing can be found in the institutional and / or clinical laboratory manual. Serum samples will be analyzed by a validated method for ADA determination.

[0253] Example 1.5 - Adverse Events Adverse event collection

[0189] An AE is defined as any untoward medical occurrence in a patient or clinical trial subject receiving a medicinal product that does not necessarily have a causal relationship to the administration of the medicinal product. An AE is therefore any untoward and unintended sign (including new, clinically significant abnormalities in laboratory findings), symptom, or disease that is temporally related to the medicinal product, whether or not related to the medicinal product. An AE is considered treatment-emergent if it occurs after the first dose of the investigational product (including during the infusion) and within 28 days of the subject's last dose of the investigational product.

[0254] All AEs will be collected from the time the informed consent form is signed through the follow-up period (Table 1). This includes events occurring during the screening phase of the study, with or without administration of study drug. When possible, a diagnosis should be recorded from the list of symptoms. If no diagnosis has been made, each symptom should be listed individually. All AEs should be recorded on the appropriate AE page in the eCRF and source documents.

[0255]

[0191] All AEs must be followed until termination, whether or not the subject is still in the study. Termination indicates that the outcome is reached, stabilization is achieved (i.e., the investigator does not expect any further improvement or worsening of the event), or the event is otherwise explained. Medical tests and consultations will be performed, where appropriate, to allow for documentation of resolution of the event.

[0256]

[0192] Lack of efficacy, including worsening of symptoms, disease progression, or lack of improvement, should not be recorded as an AE unless they meet the definition of an SAE criteria. Signs and symptoms of AOSD tracked as part of efficacy evaluation, e.g., conditions listed in the modified Pouchot score, should not be captured as AEs unless they meet the definition of an SAE.

[0257]

[0193] AEs that change in severity over time should be recorded in the eCRF once at their highest severity, with two exceptions. The first exception is a worsening of a non-AOSD-related pretreatment event after initiation of study drug, which should be recorded as a new AE. For example, if a subject experiences mild intermittent headache before receiving study drug, but the headache intensity increases to moderate after the first dose of study drug, a new AE of moderate intermittent headache should be recorded in the source document and eCRF. The second exception is an AE that starts as a non-serious event and later meets the definition of an SAE, which should be entered once for the non-serious part of the AE and then recorded again as a new event with the start date of becoming severe.

[0258] Severity of the adverse event Medical assessment of the clinical severity of AEs is determined using definitions outlined in the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (published November 27, 2017 by the U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute). Grade 1 is defined as mild; asymptomatic or mild symptoms; or clinical or diagnostic observation only; or not requiring intervention. Grade 2 is defined as moderate; or requiring minimal local or non-invasive intervention; or age-appropriate limitation in non-self-care activities of daily living (ADLs). Grade 3 is defined as severe or medically significant but not immediately life-threatening; or requiring hospitalization or prolonged hospitalization; or disabling / incapacitating; or limitation in self-care ADLs. Grade 4 is defined as life-threatening consequences; or requiring urgent intervention. Grade 5 is AE-related death.

[0259]

[0195] The above grading guidelines should be used whenever possible. For AEs that cannot be graded by use of the CTCAE, severity should be graded using mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), and death (Grade 5).

[0260]

[0196] For a complete description of CTCAE terminology and non-personal and personal ADLs, please refer to the CTCAE document listed above. It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity, whereas an SAE is an AE that meets serious criteria.

[0261] Relevance Classification

[0197] The investigator must assess each AE for relevance to the study drug. The investigator should determine, in their medical judgment, whether there is a reasonable possibility that the event was caused by the study drug. If there is no valid reason to suggest a relationship, the AE should be classified as "unrelated." Otherwise, the AE should be classified according to the guidelines below. The causality assessment must be documented in the source documents and eCRF (Table 4).

[0262] [Table 4]

[0263] Outcomes at last observation

[0198] Outcome at the last observation will be classified as recovered / resolved; recovered / resolved with sequelae; recovering / resolving; not recovered / not resolved; fatal; or unknown.

[0264] Reporting of serious adverse events

[0199] 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 becoming aware of the SAE. The Investigator or designee must complete, sign, and date the appropriate SAE form and verify the accuracy of the information by comparing it with the corresponding source documents. This information shall be sent to the CRO Pharmacovigilance Department.

[0265] Definition of serious adverse events

[0200] An SAE is any untoward medical occurrence, at any dose, whether or not considered related to the investigational drug, that results in death; is life-threatening; requires hospitalization or an extension of an existing hospitalization; results in persistent or significant incapacity / inability to perform; is a congenital anomaly; or is a significant medical event.

[0266]

[0201] Note that the term "life-threatening" in the definition of "serious" refers to an event where the subject was at risk of death at the time of the event, and not to an event that, hypothetically, would have resulted in death if more severe.

[0267]

[0202] Note that hospitalization is defined as a 24-hour or overnight stay in the hospital. Elective hospitalizations to treat conditions that existed prior to exposure to the study drug or hospitalizations for diagnostic evaluation of an AE do not qualify as conditions or events as SAEs. Additionally, an overnight stay in the hospital without a medical background solely due to transportation, organization, or housing issues need not be considered an SAE.

[0268]

[0203] Note that a congenital anomaly in an infant born to a mother exposed to the investigational drug during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject receiving the investigational drug is not considered an SAE unless the investigational drug is suspected to have interacted with a contraceptive method to result in the pregnancy.

[0269]

[0204] Note that medical and scientific judgment should be used in determining whether it is appropriate to consider other circumstances as serious, such as a significant medical event that is not immediately life-threatening or does not result in death or hospitalization, but may endanger the subject, or may require intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are allergic bronchospasm requiring intensive care in the emergency room or at home, blood disorders or seizures that do not result in hospitalization, or drug dependence or abuse.

[0270] Serious adverse events collection period

[0205] All SAEs, regardless of study relatedness, will be collected from the time the subject signs the informed consent form until the subject's last visit (clinic visit or telephone survey). The investigator or designee must promptly report all SAEs to the CRO within 24 hours of first becoming aware of the event.

[0271]

[0206] Any SAE, regardless of its relationship to study drug, that occurs during the study period but is not detected by the study site until after the end of the study must be reported to the CRO within 24 hours of first noticing the event.

[0272] Onset and resolution dates of serious adverse events

[0207] The onset date of an SAE is defined as the date on which the seriousness criteria are met. An AE that begins as a non-serious event and later meets the definition of an SAE should be entered once for the non-serious portion of the AE and then recorded again as a new event with the onset date of the seriousness.

[0273]

[0208] The resolution date is the date when the outcome is reached, stabilization is achieved (i.e., the investigator does not expect any further improvement or worsening of the event), or the event is otherwise described.

[0274] Fatal outcome

[0209] Fatal should be designated only as the outcome when an AE results in death. If more than one AE may be associated with a subject's death, the outcome of death should be presented for each such AE.

[0275] Any AE resulting in the death of a subject must be checked as fatal as the outcome with the date of death recorded as the date of disappearance. AEs resulting in death must be reported as SAEs within 24 hours if not already reported as such.

[0276]

[0211] For other AEs that did not contribute to the subject's death and were ongoing at the time of death, the outcome should not be considered as resolved and the date of resolution will not be recorded.

[0277] Adverse events of particular interest

[0212] The following events are considered AEs of special interest during this study: Immunosuppression (decreased white blood cell count, thrombocytopenia, anemia).

[0278] pregnancy All women of childbearing potential participating in the study, and men with female partners of childbearing potential, should be counseled about the need to use highly effective contraceptive methods throughout the study and for 28 days after the last dose of study drug, and the importance of avoiding pregnancy while participating in the study. Highly effective contraceptive methods are defined as those that, when used consistently and correctly, result in a low failure rate (i.e., <1% per year), such as oral / injectable / insertive / implantable / transdermal contraceptives, condom-diaphragm combinations, condom-spermicide combinations, diaphragm-spermicide combinations, intrauterine hormone-releasing systems or intrauterine devices (IUDs), or abstinence. Contraception is not required if at least 6 weeks have passed since sterilization, defined as hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy; and men who have been vasectomized. Contraception is not required if women are postmenopausal (physiological amenorrhea for 12 consecutive months and age ≥ 51 years).

[0279]

[0214] Women and men with female partners should be instructed to contact the investigator or study personnel immediately if pregnancy occurs or is suspected.

[0280] Pregnancy testing will be performed in all women according to the assessment schedule (Table 1). Women who are found to be pregnant at screening will be removed from the study and considered a screening dropout. Women who become pregnant after receiving study drug will be asked to discontinue the study and to perform an end-of-study evaluation visit whenever possible after pregnancy is discovered.

[0281]

[0216] The Investigator must report the pregnancy of any female (study participant or female partner of a male study participant) who becomes pregnant during study drug treatment or within 28 days of discontinuation of study drug (permission must be obtained from the pregnant female partner of a male patient to follow the pregnancy to conclusion and report the outcome). Pregnancy must be reported to the CRO within 24 hours of pregnancy discovery using the "Pregnancy Data Collection Form" to the same fax and email address as the SAE report. The Investigator should contact a designated individual who will receive notification of the pregnancy and record any pregnancy related information on the "Pregnancy Form" / other prescribed form provided by the Sponsor or its designee.

[0282]

[0217] The Investigator is also responsible for following the pregnancy until delivery or termination. These findings must be reported on the Pregnancy Data Collection Form and sent to a designated person. The event meets the SAE criteria only if it results in spontaneous abortion or congenital anomaly.

[0283] Reporting to regulatory authorities, institutional review boards / ethics committees and institutions

[0218] The sponsor or its designee is responsible for notifying the relevant regulatory authorities and, if applicable, the US central Institutional Review Board (IRB) of any relevant unanticipated SAEs.

[0284]

[0219] Additionally, the sponsor or its designee is responsible for notifying the validation site(s) of all relevant unanticipated SAEs that occur during all interventional studies throughout the development program.

[0285]

[0220] Investigators are responsible for notifying the Institutional IRB, Institutional Review Committee (EC), or relevant Institutional Regulatory Authority, as appropriate, of all SAEs that occur at their institution.

[0286] Example 1.6 - Overdoses and Medication Errors

[0221] Overdoses or medication errors of the investigational drug as defined below (Table 5) must be reported to the Sponsor using the SAE reporting procedures outlined above, regardless of whether they result in 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 results in an SAE.

[0287] [Table 5]

[0288] Example 1.7 - Safety Review Board

[0222] A Safety Review Committee (SRC) is involved in the conduct of this study. The SRC consists of representatives from the sponsor and study sites, including one medically qualified member from each participating site. The SRC is responsible for monitoring the progress of the clinical trial and the safety of participating subjects.

[0289] Approximately 12 subjects are planned to be enrolled in two cohorts. The first cohort of six subjects will receive, and have received, ANTIBODY A at a dose of 7 mg / kg (maximum 500 mg) IV at baseline, week 4, and week 8. Twenty-eight days after the sixth subject in the first cohort completes the first dose of ANTIBODY A, safety for the first cohort will be evaluated by the SRC, specifically evaluating AEs, SAEs, and laboratory values.

[0290]

[0224] If the first cohort experiences more than one SAE due to Antibody A, a second cohort of six subjects will be administered 4 mg / kg (maximum 300 mg) IV at baseline, week 4, and week 8.

[0291]

[0225] If one SAE attributable to Antibody A is observed in the first cohort, the SRC will evaluate the safety information and decide whether to expand the number of subjects in the first cohort or proceed with dose escalation in subjects in the second cohort.

[0292]

[0226] If there are no SAEs attributable to Antibody A, the SRC will decide whether to proceed with dose escalation in the second cohort of 6 subjects. The dose escalation regimen is 14 mg / kg (max 1000 mg) IV at baseline, week 4, and week 8. If, after dose escalation, the second cohort experiences one SAE attributable to Antibody A, the SRC will evaluate the safety information and decide whether to continue the subject at the 14 mg / kg (max 1000 mg) dose or drop to the previous 7 mg / kg (max 500 mg) dose. If, after dose escalation, the second cohort experiences more than one SAE attributable to Antibody A, the subject will be dropped to the previous 7 mg / kg (max 500 mg) dose.

[0293] Example 1.8 - Statistics Approximately 12 subjects are planned to be enrolled. Antibody A will be investigated in AOSD patients for the first time in this study. Therefore, the sample size is based on feasibility and not hypothesis testing.

[0294]

[0228] This study has the following populations of interest: the "Enrollment Population" includes all subjects who are enrolled; and the "Safety Population" includes all subjects who are enrolled and receive at least one dose of treatment during the trial.

[0295] This section provides an overview of the planned statistical analyses. Further details regarding data handling, analysis methods, and presentation of results will be provided in the "Statistical Analysis Plan" (SAP) for this study. The SAP will be finalized prior to database lock.

[0296]

[0230] All efficacy, safety, PK, and PD variables will be summarized using descriptive statistics. Descriptive statistics for continuous data will include number of subjects (n), mean, standard deviation (SD), median, minimum, and maximum. Summaries of change from baseline variables will include only subjects with both baseline values ​​and corresponding values ​​at the time points of interest. For all variables, baseline will be defined as the last assessment prior to the first dose of study drug. Descriptive statistics for categorical data will include frequencies and percentages. Where appropriate, descriptive statistics may be expressed with 95% confidence intervals. All descriptive summaries will be generated by Antibody A dose level and will include all categories.

[0297]

[0231] The disposition of all subjects enrolled in the study will be summarized by dose level and completion / discontinuation status. Subjects discontinuing the study early will be summarized by dose level and reason for discontinuation. The number of subjects in each analysis set will also be summarized by dose level.

[0298]

[0232] All subject data will be reviewed for occurrence of protocol deviations. Prior to database lock, all protocol deviations will be reviewed and classified for their potential impact on study outcomes.

[0299]

[0233] Demographic and baseline data analyses will be performed for the safety population. Demographic variables include age, sex, race, ethnicity, height, weight, and body mass index.

[0300]

[0234] Demographics and other baseline characteristics will be summarized by dose level using descriptive statistics.

[0301]

[0235] Medications are coded using the World Health Organization Drug Dictionary. Premedications and concomitant medications are summarized by dose level.

[0302]

[0236] Exposure to study drug will be summarized by dose level using descriptive statistics. Subjects will be summarized according to cumulative exposure.

[0303]

[0237] Summary compliance data is not applicable to this study since the study drug was administered by IV infusion.

[0304]

[0238] Safety analyses will be performed using data from the safety population. Safety variables will include TEAEs, clinical laboratory values, and vital signs. Unless otherwise stated, formal inferential analyses on safety variables will not be performed.

[0305] Adverse events will be coded using the Medical Dictionary for Clinical Practice (MedDRA). An AE is considered treatment-emergent if it occurs after the first dose of study drug (including during the infusion) and within 28 days after the subject's last dose of study drug.

[0306]

[0240] The overall incidence of subjects with at least one AE is summarized by dose level. The incidence of TEAEs is summarized by dose level, system organ class (SOC), and preferred term (PT), with each subject counted only once by SOC and PT. Similar summaries are made for SAEs and AEs leading to discontinuation. The maximum intensity of AEs and their maximum association with study drug are also summarized by dose level, SOC, and PT.

[0307]

[0241] Laboratory values ​​are compared to normal ranges and clinically significant levels are noted. Summaries note the frequency of abnormal values ​​and within-subject changes observed during the study.

[0308]

[0242] Narrative summaries of all reported values ​​and changes from baseline will be summarized by laboratory category, dose level, and visit.

[0309]

[0243] Vital signs will be reviewed for changes during the study that may be attributable to exposure to the study drug.

[0310]

[0244] Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, weight, and temperature) will be summarized by parameter, dose level, and visit using appropriate descriptive statistics.

[0311]

[0245] All efficacy endpoints will be summarized by dose level and visit using descriptive statistics.

[0312]

[0246] All PK parameters will be summarized using descriptive statistics by dose level and visit. Descriptive statistics for serum concentrations include n, number of subjects with concentrations below the lower limit of quantification (BLQ), mean, SD, coefficient of variation, median, minimum, and maximum. For descriptive summaries, serum concentrations reported as BLQ will be set to zero.

[0313]

[0247] All PD parameters will be summarized by dose level and visit.

[0314]

[0248] The incidence of ADAs will be summarized by dose level and visit.

[0315]

[0249] No interim analyses are planned for this study. EXAMPLES

[0316] Example 2 - Results from a Phase 1b, multicenter, open-label study to evaluate the safety and tolerability, efficacy, pharmacokinetics, and pharmacodynamics of Antibody A in subjects with Adult-onset Still's Disease

[0250] Presented in Example 2 herein are certain results of studies conducted according to the methods described in Example 1.

[0317]

[0251] The first cohort of 6 patients, the 7 mg / kg cohort, completed the study as described in Example 1. No serious adverse events attributable to Antibody A were observed in this cohort.

[0318]

[0252] Some patients in the first cohort experienced a reduction in key inflammatory markers. Figure 1 shows the CRP concentrations by visit for four patients in the first cohort. Figures 2A and 2B show the ferritin concentrations by visit for three patients in the first cohort (two patients in Figure 2A; one patient in Figure 2B). Figure 3 shows the modified Pouchot scores by visit for three patients in the first cohort. Figure 4 shows the Physician Global Assessment (PhGA) scores by visit for three patients in the first cohort. Figure 5 shows the Patient Global Assessment (PtGA) scores by visit for three patients in the first cohort.

[0319]

[0253] The second cohort will be treated according to Example 1: 14 mg / kg group. EXAMPLES

[0320] Example 3 - Study to evaluate the safety and tolerability, efficacy, pharmacokinetics, and pharmacodynamics of Antibody A in subjects with systemic-onset juvenile idiopathic arthritis

[0254] Antibody A will be tested in patients with systemic-onset juvenile idiopathic arthritis. Subjects will be examined according to a similar protocol as described in Example 1.

[0321]

[0255] The following table provides the sequences referenced in this application.

[0322] [Table 6-1]

[0323] [Table 6-2]

[0324] [Table 6-3]

[0325] [Table 6-4]

[0326]

Table 6-5

[0327]

Table 6-6

[0328]

Table 6-7

[0329]

Table 6-8

[0330]

Table 6-9

[0331]

Table 6-10

[0332]

Table 6-11

[0333]

Table 6-12

[0334]

Table 6-13

[0335]

Table 6-14

[0336]

Table 6-15

[0337]

Table 6-16

[0338]

Table 6-17

[0339]

Table 6-18

[0340]

Table 6-19

[0341]

Table 6-20

[0342]

Table 6-21

[0343]

Table 6-22

[0344]

Table 6-23

[0345]

Table 6-24

[0346]

Table 6-25

Claims

1. 1. A method of treating Adult-onset Still's Disease (AOSD) or Systemic-onset Juvenile Idiopathic Arthritis (SoJIA), comprising administering to a human subject diagnosed with AOSD or SoJIA an effective amount of an anti-IL-18 antibody, wherein the anti-IL-18 antibody has the following six CDRs: (a) a heavy chain CDR having the amino acid sequence of SEQ ID NO: 122; (b) a heavy chain CDR having the amino acid sequence of SEQ ID NO: 123; (c) a heavy chain CDR having the amino acid sequence of SEQ ID NO: 124; (d) a light chain CDR having the amino acid sequence of SEQ ID NO: 126; (e) a light chain CDR having the amino acid sequence of SEQ ID NO: 127; and (f) a light chain CDR having the amino acid sequence of SEQ ID NO:

128. wherein the anti-IL-18 antibody is administered at a dose of 4 mg / kg, 7 mg / kg, or 14 mg / kg.

2. 10. The method of claim 1, wherein the subject is diagnosed with AOSD based on having five or more of the following criteria, two of which are major criteria: (a) Major standards i. Fever > 39°C for more than one week ii. Joint pain or arthritis lasting for more than 2 weeks iii. Typical rash iv. White blood cells >10,000 mm with >80% polymorphonuclear cells ３ (b) Minor criteria v. sore throat vi. Recent onset of significant lymphadenopathy vii. Hepatomegaly or splenomegaly viii. Abnormal liver function tests ix. Antinuclear antibody (IF) and rheumatoid factor (IgM) tests negative.

3. 3. The method of claim 1 or claim 2, wherein the subject reports a recurrence of fever > 38°C within the last 5 days of the screening and baseline visit.

4. The method of any one of claims 1 to 3, wherein if the subject is receiving treatment with NSAIDs, the subject has been receiving a stable dose for at least 48 hours prior to the baseline visit.

5. The method of any one of claims 1 to 4, wherein if the subject is undergoing treatment with a glucocorticoid, the subject has been receiving a stable dose for at least 48 hours prior to the baseline visit.

6. The method of any one of claims 1 to 5, wherein if the subject is being treated with a conventional DMARD, the subject has been receiving a stable dose for at least 12 weeks prior to the baseline visit.

7. The method of any one of claims 1 to 6, wherein if the subject is undergoing treatment with a biologic DMARD, the subject has undergone a required drug-off period prior to the baseline visit, the required drug-off period being as follows: e) anakinra - 1 week; f) etanercept, rilonacept - 4 weeks; g) adalimumab, certolizumab, infliximab, golimumab, abatacept, tocilizumab, and canakinumab - 8 weeks; and h) Rituximab - 36 weeks.

8. The method of any one of claims 1 to 7, wherein the subject does not have a serum creatinine concentration of > 1.5 mg / dl.

9. 9. The method of any one of claims 1 to 8, wherein the subject does not have hemoglobin < 10 g / dl, neutrophils < 1,500 / μl, and / or platelets < 75,000 / μl.

10. 10. The method of any one of claims 1 or 3-9, including a method for treating SoJIA.

11. The method of any one of claims 1 to 10, wherein the subject has elevated free or total serum IL-18 levels.

12. The method of any one of claims 1 to 11, wherein the level of serum IL-18 is measured before administration of the anti-IL-18 antibody.

13. The method according to any one of claims 1 to 12, wherein the level of serum IL-18 is measured after administration of an anti-IL-18 antibody, optionally as a marker of the effectiveness of the treatment.

14. 14. The method of any one of claims 1 to 13, wherein the level of serum IL-18 is elevated compared to the level in a subject without AOSD or SoJIA, or compared to a negative control.

15. The method of any one of claims 1 to 14, wherein the level of serum IL-18 in the subject is measured after administration of an anti-IL-18 antibody as a marker of the effectiveness of the treatment.

16. The method of any one of claims 1 to 15, wherein the level of serum IL-18 is free IL-18, and optionally the level of free IL-18 is calculated.

17. The method of any one of claims 1 to 15, wherein the level of serum IL-18 is total IL-18.

18. The method of any one of claims 1 to 16, wherein the subject has elevated serum free IL-18.

19. The method of any one of claims 1 to 15 or 17, wherein the subject has elevated serum total IL-18.

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

121.

21. The method of any one of claims 1 to 20, wherein the anti-IL-18 antibody comprises a VH domain having an amino acid sequence identical to the complete sequence of SEQ ID NO:

121.

22. The method of any one of claims 1 to 21, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence that is at least 90% identical to the complete sequence of SEQ ID NO:

125.

23. The method of any one of claims 1 to 22, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence identical to the complete sequence of SEQ ID NO:

125.

24. 24. The method of any one of claims 1 to 23, wherein the anti-IL-18 antibody comprises an antibody VH domain and an antibody VL domain, wherein the amino acid sequence of the antibody VH domain is at least 90% identical to the complete sequence of SEQ ID NO: 121 and the antibody VL domain is at least 90% identical to the complete sequence of SEQ ID NO:

125.

25. The method of any one of claims 1 to 24, wherein the anti-IL-18 antibody is administered in the form of a pharma- ceutically acceptable composition.

26. The method of any one of claims 1 to 25, wherein the anti-IL-18 antibody is administered for at least 16 weeks.

27. The method of any one of claims 1 to 26, wherein the anti-IL-18 antibody is administered intravenously.

28. The method of any one of claims 1 to 26, wherein the anti-IL-18 antibody is administered subcutaneously.

29. 29. The method of any one of claims 1 to 28, 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.

30. 30. The method of any one of claims 1 to 29, wherein the subject achieves resolution of fever.

31. The method of any one of claims 1 to 30, wherein the subject achieves a reduction in CRP.

32. The method of any one of claims 1-31, wherein the subject achieves a ≧50% reduction in CRP from baseline by week 4.

33. The method of any one of claims 1-32, wherein the subject achieves a ≧50% reduction in CRP from baseline by week 12.

34. The method of any one of claims 1 to 33, wherein the subject achieves a reduction in serum IL-18 levels.

35. The method of any one of claims 1 to 34, wherein the subject achieves a reduction in serum total IL-18 levels.

36. The method of any one of claims 1 to 34, wherein the subject achieves a reduction in serum free IL-18 levels.

37. The method of any one of claims 1 to 36, wherein the subject has an undetectable level of serum IL-18 at about 4 weeks after administration of the anti-IL-18 antibody.

38. The method of any one of claims 1 to 37, wherein the subject has an undetectable level of serum IL-18 at about 12 weeks after administration of the anti-IL-18 antibody.

39. The method of any one of claims 1 to 38, wherein the subject has an undetectable level of serum total IL-18 at about 4 weeks after administration of the anti-IL-18 antibody.

40. The method of any one of claims 1 to 39, wherein the subject has an undetectable level of serum total IL-18 at about 12 weeks after administration of the anti-IL-18 antibody.

41. The method of any one of claims 1 to 38, wherein the subject has an undetectable level of serum free IL-18 at about 4 weeks after administration of the anti-IL-18 antibody.

42. The method of any one of claims 1 to 39, wherein the subject has an undetectable level of serum free IL-18 at about 12 weeks after administration of the anti-IL-18 antibody.

43. 43. The method of any one of claims 1 to 42, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by physician and / or patient global assessment of disease activity assessed by visual analog scale (VAS).

44. 44. The method of any one of claims 1 to 43, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by physician and / or patient global assessment of disease activity assessed by visual analog scale (VAS) at least about 4 weeks after administration of the anti-IL-18 antibody.

45. 45. The method of any one of claims 1-44, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as measured by physician and / or patient global assessment of disease activity assessed by visual analog scale (VAS) at least about 12 weeks after administration of the anti-IL-18 antibody.

46. 46. ​​The method of any one of claims 1-45, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a modified Pouchot score.

47. 47. The method of any one of claims 1-46, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a modified Pouchot score about 4 weeks after administration of the anti-IL-18 antibody.

48. 48. The method of any one of claims 1-47, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a modified Pouchot score at about 12 weeks after administration of the anti-IL-18 antibody.

49. 49. The method of any one of claims 1-48, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using the DAS28-CRP score.

50. 50. The method of any one of claims 1-49, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a DAS28-CRP score about 4 weeks after administration of the anti-IL-18 antibody.

51. 51. The method of any one of claims 1-50, wherein the subject exhibits a reduction in signs and symptoms of AOSD or SoJIA as assessed using a DAS28-CRP score at about 12 weeks after administration of the anti-IL-18 antibody.

52. The method of any one of claims 1 to 51, wherein the subject experiences a decrease in serum ferritin.

53. The method of any one of claims 1 to 52, wherein the subject experiences a decrease in serum ferritin at about 4 weeks after administration of the anti-IL-18 antibody.

54. The method of any one of claims 1 to 53, wherein the subject experiences a decrease in serum ferritin at about 12 weeks after administration of the anti-IL-18 antibody.

55. 55. The method of any one of claims 1 to 54, wherein the subject experiences a decrease in erythrocyte sedimentation rate (ESR).

56. The method of any one of claims 1 to 55, wherein the subject experiences a decrease in erythrocyte sedimentation rate (ESR) about 4 weeks after administration of the anti-IL-18 antibody.

57. The method of any one of claims 1 to 56, wherein the subject experiences a decrease in erythrocyte sedimentation rate (ESR) about 12 weeks after administration of the anti-IL-18 antibody.

58. 58. The method of any one of claims 1 to 57, further comprising the step of administering one or more additional therapeutically active agents.

59. 59. The method of claim 58, wherein the one or more additional therapeutically active agents comprise at least one of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, systemic glucocorticoids, and conventional systemic disease-modifying antirheumatic drugs (DMARDs).

60. 60. The method of claim 59, wherein the conventional systemic disease-modifying antirheumatic drug (DMARD) is methotrexate.

61. 60. The method of claim 59, wherein the corticosteroid is prednisone.

62. A kit for use in the method of any one of claims 1 to 61 comprising an anti-IL-18 antibody and reagents for carrying out the method.

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