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WO2023121643A1 - Méthodes et traitement de la maladie de still chez l'adulte et de la forme systémique de l'arthrite idiopathique juvénile impliquant des anticorps dirigés contre il-18 - Google Patents

Méthodes et traitement de la maladie de still chez l'adulte et de la forme systémique de l'arthrite idiopathique juvénile impliquant des anticorps dirigés contre il-18 Download PDF

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Publication number
WO2023121643A1
WO2023121643A1 PCT/US2021/064357 US2021064357W WO2023121643A1 WO 2023121643 A1 WO2023121643 A1 WO 2023121643A1 US 2021064357 W US2021064357 W US 2021064357W WO 2023121643 A1 WO2023121643 A1 WO 2023121643A1
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Prior art keywords
antibody
subject
weeks
serum
reduction
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Inventor
Garry A. NEIL
H. Jeffrey Wilkins
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Avalo Therapeutics Inc
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Avalo Therapeutics Inc
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Priority to PCT/US2021/064357 priority Critical patent/WO2023121643A1/fr
Priority to AU2021479973A priority patent/AU2021479973A1/en
Priority to JP2024537408A priority patent/JP2025500352A/ja
Priority to KR1020247024581A priority patent/KR20240134909A/ko
Priority to CA3243024A priority patent/CA3243024A1/fr
Priority to MX2024007616A priority patent/MX2024007616A/es
Publication of WO2023121643A1 publication Critical patent/WO2023121643A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • 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 an anti-interleukin 18 (IL- 18) neutralizing antibody.
  • AOSD adult-onset Still’s disease
  • SoJIA systemic-onset juvenile idiopathic arthritis
  • NSAIDs non-steroidal anti-inflammatory drugs
  • corticosteroids corticosteroids
  • Refractory patients are treated with immunosuppressive agents including methotrexate.
  • Patients who remain refractory may be treated empirically with biologic agents including anti-TNF antibodies (adalimumab), anakinra (anti-IL-1), or tocilizumab (anti-IL-6).
  • MAS macrophage activation syndrome
  • lymphadenopathy (Gerfaud-V al entin, M, Autoimmun Rev. Jul;13(7):708-722 (2014)), and splenomegaly (Gerfaud-V al entin, M, et al., Autoimmun Rev. Jul;13(7):708-722 (2014)) can also be present.
  • HSH hemophagocytic lymphohistiocytosis
  • Other hematological disorders that can be associated with AOSD include microangiopathic hemolytic anemia associated with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
  • Some of the treatment goals of AOSD are: control of the physical signs and symptoms of inflammation (fever, rash, morning stiffness, joint pain, and swelling); control of laboratory indices of inflammation; prevention of end organ damage, including joint injury and other major organ complications; and minimization of the risk of adverse effects of therapy, including short and long-term adverse effects of glucocorticoids.
  • SoJIA Systemic-onset juvenile idiopathic arthritis
  • SoJIA is similar to AOSD, but differs in terms of classification criteria.
  • SoJIA and AOSD are the same disease, just happening in different age groups.
  • SoJIA is a subset of juvenile idiopathic arthritis marked by more severe extra-articular manifestations (fever, cutaneous eruptions).
  • the number of sites of the body affected by the arthritis vary but affect both the small and large joints in a nearly symmetrical manner. Id. Some patients may also have adenopathy and/or hepatosplenomegaly. Id. Other symptoms such as pericarditis, pleural effusion, or serous peritonitis with abdominal pain may be present. Id. SoJIA patients typically have severe inflammatory disease with a large increase in ferritin levels and a decrease in the percentage of glycosylated ferritin. Id. Physicians often use a “clinical triad” to diagnose this disease: daily fever lasting more than 2 weeks, arthritis, and cutaneous eruptions. See Petty, R et al., J. Rheumatol.
  • IL-18 is a pro-inflammatory cytokine that plays a role in both innate and acquired immune responses. In many patients with AOSD, IL-18 is markedly elevated. Concentrations of IL- 18 have been found to be > 100,000 pg/ml in active AOSD and correlate with disease severity. (Kudela, H, et al., BMC Rheum 3:4 (2019)).
  • FIG. 1 Key markers of inflammation - C-reactive protein (CRP) measured in mg/L by visit.
  • the Y-axis is 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 in mg/L for that patient at that point in time.
  • V refers to “visit” and the number behind the “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.
  • the weeks on the X-axis (e.g., “Wk 1”) refer to assessment weeks as shown in Table 1, Schedule of Assessments, herein.
  • Figures 2A and 2B show key markers of inflammation - ferritin measured in ng/L by visit for two patients.
  • the Y-axis is ferritin concentration in 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 in ng/L for that patient at that point in time.
  • “V” refers to “visit” and the number behind the “V” refers to the visit number.
  • “V3” refers to visit 3.
  • the weeks on the X-axis (e.g., “Wk 1”) refer to assessment weeks as shown in Table 1, Schedule of Assessments, herein.
  • “Early Term” refers to early termination. “F/U” refers to follow-up visit.
  • Figure 2B shows key markers of inflammation - ferritin measured in ng/L by visit for one patient, patient 012-01.
  • the Y-axis is ferritin concentration in ng/mL.
  • the X-axis refers to time.
  • the line refers to data from one patient.
  • the patient is assigned a number. Each number next to each data point on the line graph indicates the ferritin concentration in ng/L for the patient at that point in time.
  • “V” refers to “visit” and the number behind the “V” refers to the visit number. For example, “V3” refers to visit 3.
  • the weeks on the X-axis refer to assessment weeks as shown in Table 1, Schedule of Assessments, herein.
  • the data for patient 012-01 is shown separately in this figure because that patient’s ferritin concentrations were higher than that of the other patients whose data is shown in Figure 2A, and required a different scale on the Y-axis.
  • FIG. 3 Key markers of inflammation - modified Pouchot score by visit.
  • 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 behind the “V” refers to the visit number. For example, “V3” refers to visit 3. “ET” refers to early termination.
  • the weeks on the X-axis (e.g., “Wk 1”) refer to assessment weeks as shown in Table 1, Schedule of Assessments, herein.
  • Figure 4 Key markers of inflammation - physician global assessment (PhGA) measured on a visual analog scale (VAS) of 100 mm by visit.
  • the Y-axis is PhGA score measured on a VAS of 100 mm.
  • 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 behind the “V” refers to the visit number. For example, “V3” refers to visit 3.
  • “ET” refers to early termination.
  • the weeks on the X-axis e.g., “Wk 1”) refer to assessment weeks as shown in Table 1, Schedule of Assessments, herein.
  • FIG. 5 Key markers of inflammation - patient global assessment (PtGA) measured on a visual analog scale (VAS) of 100 mm by visit.
  • the Y-axis is PtGA score measured on a VAS of 100 mm.
  • 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 point in time.
  • V refers to “visit” and the number behind the “V” refers to the visit number. For example, “V3” refers to visit 3.
  • “ET” refers to early termination.
  • the weeks on the X-axis (e.g., “Wk 1”) refer to assessment weeks as shown in Table 1, Schedule of Assessments, herein.
  • the present disclosure includes, for example, any one or a combination of the following embodiments:
  • Embodiment 1 A method of treating Adult-onset Still’s disease (AOSD) or systemiconsetjuvenile 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 comprises the following six CDRs:
  • Embodiment 2 The method of embodiment 1, wherein the subject is diagnosed with
  • AOSD based on having 5 or more of the following criteria, 2 of which are major:
  • Embodiment 3 The method of embodiment 1 or embodiment 2, wherein the subject has reported a recurring fever >38°C within the last 5 days of screening and baseline visits.
  • Embodiment 4 The method of any one of embodiments 1-3, wherein if the subject is undergoing treatment with NSAIDs, the subject is on a stable dose for at least 48 hours prior to a baseline visit.
  • Embodiment 5 The method of any one of embodiments 1-4, wherein if the subject is undergoing treatment with glucocorticoids, the subject is on a stable dose for at least 48 hours prior to a baseline visit.
  • Embodiment 6 The method of any one of embodiments 1-5, wherein if the subject is undergoing treatment with conventional DMARDs, the subject is on a stable dose for at least 12 weeks prior to a baseline visit.
  • Embodiment 7 The method of any one of embodiments 1-6, wherein if the subject has received treatment with biological DMARDs, the subject has undergone the required washout period prior to a baseline visit, wherein the required washout 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.
  • Embodiment 8 The method of any one of embodiments 1-7, wherein the subject does not have a serum creatinine concentration of > 1.5 mg/dl.
  • Embodiment 9 The method of any one of embodiments 1-8, wherein the subject does not have hemoglobin ⁇ 10 g/dl, neutrophils ⁇ l,500/pl and/or thrombocytes ⁇ 75,000/pl.
  • Embodiment 10 The method of any one of embodiments 1 or 3-9, comprising a method of treating So JI A.
  • Embodiment 11 The method of any one of embodiments 1-10, wherein the subject has elevated free or total serum IL-18 levels.
  • 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.
  • Embodiment 13 The method of any one of embodiments 1-12, wherein the level of serum IL- 18 is measured after administration of the anti-IL-18 antibody, optionally as a marker for effectiveness of treatment.
  • Embodiment 14 The method of any one of embodiments 1-13, wherein the level of serum IL-18 is elevated as compared to levels in a subject without AOSD or SoJIA or as compared to a negative control.
  • Embodiment 15 The method of any one of embodiments 1-14, wherein levels of serum IL- 18 in the subject are measured after administration of the anti-IL-18 antibody as a marker for effectiveness of treatment.
  • Embodiment 16 The method of any one of embodiments 1-15, wherein the level of serum IL-18 is free IL-18, optionally wherein the level of free IL-18 is calculated.
  • Embodiment 17 The method of any one of embodiments 1-15, wherein the level of serum IL- 18 is total IL- 18.
  • Embodiment 18 The method of any one of embodiments 1-16, wherein the subject has elevated serum free IL-18.
  • Embodiment 19 The method of any one of embodiments 1-15 or 17, wherein the subject has elevated serum total IL- 18.
  • 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 full sequence of SEQ ID NO: 121.
  • 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 that is identical to the full sequence of SEQ ID NO: 121.
  • Embodiment 22 The method of any one of embodiments 1-21, wherein the anti-IL-18 antibody comprises a VL domain having an amino acid sequence that is at least 90% identical to the full sequence of SEQ ID NO: 125.
  • Embodiment 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 that is identical to the full sequence of SEQ ID NO: 125.
  • Embodiment 24 The method of any one of embodiments 1-23, 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 full sequence of SEQ ID NO: 121, and the antibody VL domain is at least 90% identical to the full sequence of SEQ ID NO: 125.
  • Embodiment 25 The method of any one of embodiments 1-24, wherein the anti-IL-18 antibody is administered in the form of a pharmaceutically acceptable composition.
  • Embodiment 26 The method of any one of embodiments 1-25, wherein the anti-IL-18 antibody is administered for a period of at least 16 weeks.
  • Embodiment 27 The method of any one of embodiments 1-26, wherein the anti-IL-18 antibody is administered intravenously.
  • Embodiment 28 The method of any one of embodiments 1-26, wherein the anti-IL-18 antibody is administered subcutaneously.
  • Embodiment 29 The method of any one of embodiments 1-28, wherein the anti-IL-18 antibody is administered once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
  • Embodiment 30 The method of any one of embodiments 1-29, wherein the subject achieves resolution of fever.
  • Embodiment 31 The method of any one of embodiments 1-30, wherein the subject achieves a reduction of CRP.
  • Embodiment 32 The method of any one of embodiments 1-31, wherein the subject achieves a reduction of CRP of >50% from baseline to week 4.
  • Embodiment 33 The method of any one of embodiments 1-32, wherein the subject achieves a reduction of CRP of >50% from baseline to week 12.
  • Embodiment 34 The method of any one of embodiments 1-33, wherein the subject achieves a reduction of serum IL- 18 levels.
  • Embodiment 35 The method of any one of embodiments 1-34, wherein the subject achieves a reduction of serum total IL-18 levels.
  • Embodiment 36 The method of any one of embodiments 1-34, wherein the subject achieves a reduction of serum free IL-18 levels.
  • Embodiment 37 The method of any one of embodiments 1-36, wherein the subject has undetectable levels of serum IL- 18 at about 4 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 38 The method of any one of embodiments 1-37, wherein the subject has undetectable levels of serum IL-18 at about 12 weeks after administration of the anti-IL- 18 antibody.
  • Embodiment 39 The method of any one of embodiments 1-38, wherein the subject has undetectable levels of serum total IL-18 at about 4 weeks after administration of the anti- IL-18 antibody.
  • Embodiment 40 The method of any one of embodiments 1-39, wherein the subject has undetectable levels of serum total IL- 18 at about 12 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 41 The method of any one of embodiments 1-38, wherein the subject has undetectable levels of serum free IL- 18 at about 4 weeks after administration of the anti- IL-18 antibody.
  • Embodiment 42 The method of any one of embodiments 1-39, wherein the subject has undetectable levels of serum free IL-18 at about 12 weeks after administration of the anti- IL-18 antibody.
  • Embodiment 43 The method of any one of embodiments 1-42, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA as measured by the Physician and/or Patient Global Assessment of disease activity assessed on a Visual Analogue Scale (VAS).
  • VAS Visual Analogue Scale
  • Embodiment 44 The method of any one of embodiments 1-43, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA as measured by the Physician and/or Patient Global Assessment of disease activity assessed on a Visual Analogue Scale (VAS) at least at about 4 weeks after administration of the anti-IL-18 antibody.
  • VAS Visual Analogue Scale
  • Embodiment 45 The method of any one of embodiments 1-44, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA as measured by the Physician and/or Patient Global Assessment of disease activity assessed on a Visual Analogue Scale (VAS) at least at about 12 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 46 The method of any one of embodiments 1-45, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the modified Pouchot score.
  • Embodiment 47 The method of any one of embodiments 1-46, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the modified Pouchot score at about 4 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 48 The method of any one of embodiments 1-47, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the modified Pouchot score at about 12 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 49 The method of any one of embodiments 1-48, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the DAS28- CRP score.
  • Embodiment 50 The method of any one of embodiments 1-49, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the DAS28- CRP score at about 4 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 51 The method of any one of embodiments 1-50, wherein the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the DAS28- CRP score at about 12 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 52 The method of any one of embodiments 1-51, wherein the subject experiences a reduction in serum ferritin.
  • Embodiment 53 The method of any one of embodiments 1-52, wherein the subject experiences a reduction in serum ferritin at about 4 weeks after administration of the anti- IL-18 antibody.
  • Embodiment 54 The method of any one of embodiments 1-53, wherein the subject experiences a reduction in serum ferritin at about 12 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 55 The method of any one of embodiments 1-54, wherein the subject experiences a reduction in erythrocyte sedimentation rate (ESR).
  • ESR erythrocyte sedimentation rate
  • Embodiment 56 The method of any one of embodiments 1-55, wherein the subject experiences a reduction in erythrocyte sedimentation rate (ESR) at about 4 weeks after administration of the anti-IL-18 antibody.
  • ESR erythrocyte sedimentation rate
  • Embodiment 57 The method of any one of embodiments 1-56, wherein the subject experiences a reduction in erythrocyte sedimentation rate (ESR) at about 12 weeks after administration of the anti-IL-18 antibody.
  • Embodiment 58 The method of any one of embodiments 1-57, further comprising administering one or more additional therapeutically active agents.
  • Embodiment 59 The method of embodiment 58, wherein the one or more additional therapeutically active agents comprises at least one of non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, systemic glucocorticoids, and conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • corticosteroids corticosteroids
  • systemic glucocorticoids systemic glucocorticoids
  • DMARDs synthetic disease-modifying anti-rheumatic drugs
  • Embodiment 60 The method of embodiment 59, wherein the conventional synthetic disease-modifying anti-rheumatic drug (DMARD) is methotrexate.
  • DMARD conventional synthetic disease-modifying anti-rheumatic drug
  • Embodiment 61 The method of embodiment 59, wherein the corticosteroid is prednisone.
  • Embodiment 62 A kit for use in a method of any one of embodiments 1-61, comprising an anti -IL- 18 antibody and reagents for carrying out the method.
  • a or “an” entity refers to one or more of that entity; for example, “a cDNA” refers to one or more cDNA or at least one cDNA.
  • a cDNA refers to one or more cDNA or at least one cDNA.
  • the terms “a” or “an,” “one or more” and “at least one” can be used interchangeably herein.
  • the terms “comprising,” “including,” and “having” can be used interchangeably.
  • a compound “selected from the group consisting of’ refers to one or more of the compounds in the list that follows, including mixtures (i.e. combinations) of two or more of the compounds.
  • an “isolated,” or “biologically pure” molecule is a compound that has been removed from its natural milieu.
  • the terms “isolated” and “biologically pure” do not necessarily reflect the extent to which the compound has been purified.
  • An isolated compound of the present invention can be obtained from its natural source, can be produced using laboratory synthetic techniques or can be produced by any such chemical synthetic route.
  • IL-18 or “Interleukin- 18” or “interferon-gamma inducing factor” or “IFN-y- inducing factor” refers to a proinflammatory cytokine encoded by the IL 18 gene that belongs to the IL-1 family of cytokines. Similar to IL-ip, it is synthesized as an inactive precursor called pro-IL-18 that is activated by cleavage by caspase-1. Pro-IL-18 is present in healthy cells and constitutively expressed by monocytes and epithelial cells. IL- 18 has roles in stimulating both adaptive and innate immune response.
  • “Elevated IL-18” as used herein refers to a level of total IL-18 detected in a subject that is higher than a normal control.
  • the normal control can be determined by those of skill in the art as applicable to the particular situation.
  • the normal control is an industry standard agreed upon by those of skill as being a level or range of levels that is typical of an individual without an IL-18-associated condition.
  • the normal control is a reference level of IL- 18 from the same individual taken at a time point, and whether the subject has elevated IL- 18 is determined based on a sample from that same individual taken at a different, typically later, time point.
  • Free IL- 18 or “free (active) IL- 18” herein refers to non-bound form IL- 18, which is the active form of IL-18. In humans, free IL-18 is neutralized (inactivated) by IL-18BP, which binds IL- 18 and inhibits its activity by interfering with its interaction with IL-18Ra.
  • “Bound IL-18,” or the like, refers to IL-18 that is bound to a natural ligand, optionally wherein the natural ligand is IL-18Ra or IL-18BP.
  • Free IL- 18 may be calculated according to known methods, e.g., Palladino et al. (2012) J. Neuroinflammation 9(206).
  • Total IL-18 refers to the total amount of free IL-18 and bound IL- 18.
  • “Serum” or “circulating” IL-18 is IL-18 that is located in the serum.
  • Undetectable levels of serum IL-18 refers to levels of IL-18 that are below the level of quantification of an assay for measuring IL-18.
  • antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.
  • the term refers to a molecule comprising at least complementarity-determining region (CDR) 1, CDR2, and CDR3 of a heavy chain and at least CDR1, CDR2, and CDR3 of a light chain, wherein the molecule is capable of binding to antigen.
  • CDR complementarity-determining region
  • CDR3 complementarity-determining region
  • a “set of CDRs” comprises CDR1, CDR2 and CDR3.
  • a set of HCDRs refers to HCDR1, HCDR2 and HCDR3
  • a set of LCDRs refers to LCDR1, LCDR2 and LCDR3.
  • a “set of CDRs” includes HCDRs and LCDRs.
  • the term antibody includes, but is not limited to, fragments that are capable of binding antigen, such as Fv, single-chain Fv (scFv), Fab, Fab’, and (Fab’)2.
  • the term antibody also includes, but is not limited to, chimeric antibodies, humanized antibodies, human antibodies, and antibodies of various species such as mouse, cynomolgus monkey, etc.
  • heavy chain refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence.
  • a heavy chain comprises at least a portion of a heavy chain constant region.
  • 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.
  • heavy chain variable region refers to a region comprising a heavy chain complementarity determining region (CDR) 1, framework region (FR) 2, CDR2, FR3, and CDR3 of the heavy chain.
  • a heavy chain variable region also comprises at least a portion of an FR1 and/or at least a portion of an FR4.
  • a heavy chain CDR1 corresponds to Kabat residues 31 to 35;
  • a heavy chain CDR2 corresponds to Kabat residues 50 to 65;
  • a heavy chain CDR3 corresponds to Kabat residues 95 to 102. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.).
  • 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.
  • light chain variable region refers to a region comprising a light chain CDR1, FR2, HVR2, FR3, and HVR3.
  • a light chain variable region also comprises an FR1 and/or an FR4.
  • a light chain CDR1 corresponds to Kabat residues 24 to 34;
  • a light chain CDR2 corresponds to Kabat residues 50 to 56;
  • a light chain CDR3 corresponds to Kabat residues 89 to 97. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.).
  • a “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • a chimeric antibody refers to an antibody comprising at least one variable region from a first species (such as mouse, rat, cynomolgus monkey, etc.) and at least one constant region from a second species (such as human, cynomolgus monkey, etc.).
  • a chimeric antibody comprises at least one mouse variable region and at least one human constant region.
  • a chimeric antibody comprises at least one cynomolgus variable region and at least one human constant region. In some embodiments, all of the variable regions of a chimeric antibody are from a first species and all of the constant regions of the chimeric antibody are from a second species.
  • a “humanized antibody” refers to an antibody in which at least one amino acid in a framework region of a non-human variable region has been replaced with the corresponding amino acid from a human variable region.
  • a humanized antibody comprises at least one human constant region or fragment thereof.
  • a humanized antibody is an Fab, an scFv, a (Fab')2, etc.
  • a “human antibody” as used herein refers to antibodies produced in humans, antibodies produced in non-human animals that comprise human immunoglobulin genes, such as XenoMouse®, and antibodies selected using in vitro methods, such as phage display, wherein the antibody repertoire is based on human immunoglobulin sequences.
  • leader sequence refers to a sequence of amino acid residues located at the N terminus of a polypeptide that facilitates secretion of a polypeptide from a mammalian cell.
  • a leader sequence may be cleaved upon export of the polypeptide from the mammalian cell, forming a mature protein.
  • Leader sequences may be natural or synthetic, and they may be heterologous or homologous to the protein to which they are attached.
  • Percent (%) amino acid sequence identity and “homology” with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • inhibitors refer to a decrease or cessation of any event (such as protein ligand binding) or to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic.
  • To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function, and/or amount as compared to a reference. It is not necessary that the inhibition or reduction be complete.
  • by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20% or greater.
  • by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater.
  • by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater.
  • sample or “subject sample” or “biological sample” generally refers to a sample which may be tested for a particular molecule. Samples may include but are not limited to cells, bone marrow, body fluids, including blood, serum, plasma, urine, saliva, stool, tears, pleural fluid and the like.
  • agent and “test compound” are used interchangeably herein and denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Biological macromolecules include siRNA, shRNA, antisense oligonucleotides, peptides, peptide/DNA complexes, and any nucleic acid based molecule which exhibits the capacity to modulate the activity of the SNP containing nucleic acids described herein or their encoded proteins.
  • a “subject” can be mammalian. In any of the embodiments involving a subject, the subject can be human. In any of the embodiments involving a subject, the subject can be a cow, pig, monkey, sheep, dog, cat, fish, or poultry.
  • a “pediatric” subject herein is a human of less than 18 years of age, whereas an “adult” subject is 18 years or older.
  • composition may refer to a composition comprising the anti-IL-18 antibody in formulations with a wide variety of pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to refers to an ingredient in a pharmaceutical formulation or composition, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, and/or preservative.
  • Treatment 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.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i. e. , not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • an effective amount refers to an amount of a drug effective for treatment of a disease or disorder in a subject, such as to partially or fully relieve one or more symptoms.
  • an effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • AOSD Alzheimer's disease
  • classification criteria defined as having at least five or more of fever > 39°C, lasting 1 week or longer; arthralgia or arthritis, lasting 2 weeks or longer; typical rash; leukocytes > 10,000 mm 3 with >80% polymorphonuclear cells; sore throat; recent development of significant lymphadenopathy; hepatomegaly or splenomegaly; abnormal liver function tests; negative tests for antinuclear antibody (IF) and rheumatoid factor (IgM); and at least two or more of fever > 39°C, lasting 1 week or longer; arthralgia or arthritis, lasting 2 weeks or longer; typical rash; or leukocytes > 10,000 mm 3 with >80% polymorphonuclear cells.
  • IF antinuclear antibody
  • IgM rheumatoid factor
  • PtGA or “Patient Global Assessment of Disease Activity” measured on a visual analog scale (VAS) is a measure of the patient’s disease activity as assessed by the patient on a 100 mm scale.
  • VAS visual analog scale
  • some Patient Global assessment of Disease Activity scales ask the patient to evaluate their disease activity based on a question such as: “Considering all the ways your AOSD affects you, rate how well you are doing on the following scale” of 0 to 100. A score of “0 mm” often means the patient is doing very well /has no evidence of disease and a score of “100 mm” indicates the patient is doing very poorly /has very severe disease activity.
  • PhGA 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 100 mm scale.
  • a score of “0 mm” often means the patient is doing very well/has no evidence of disease and a score of “100 mm” indicates the patient is doing very poorly /has very severe disease activity.
  • the physician performing the assessment must not be aware of the specific PtGA when performing his/her own assessment of the patient.
  • CRP refers to C-reactive protein, a protein in the blood. It is made by the liver and it is sent into the bloodstream in response to inflammation. It is measured in mg/L. CRP levels rise and fall depending on inflammation levels, with greater inflammation corresponding to higher CRP levels. Results are typically compared to the normal value ranges, but the normal range values may vary slightly among different laboratories.
  • DAS28-CRP Disease Activity Score-28 for Rheumatoid Arthritis with CRP refers to a score calculated based on information about the following disease variables: the number of swollen joints and tender joints assessed using 28-joint count (TJC28 and SJC28); PtGA (Patient Global Assessment of Disease Activity) measured on a VAS (visual analog scale) of 100 mm; and CRP measured in mg/L.
  • the DAS28-CRP score is calculated using the following formula: 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+l) + 0.014 * PtGA + 0.96.
  • the DAS28 score ranges from 0 to 10, with higher scores indicating a more severe current activity of the disease.
  • the DAS28 score may also be categorized into disease activity states according to the cut-off values as follows: high disease activity: >5.1; moderate disease activity: >3.2 to ⁇ 5.1; low disease activity: >2.6 to ⁇ 3.2; remission: ⁇ 2.6.
  • corticosteroids refers to a type of anti-inflammatory drug. They are man-made drugs that closely resemble cortisol, a hormone that the adrenal glands naturally produce. A few examples of corticosteroids include cortisone and prednisone. Glucocorticosteroids (also referred to as glucocorticoids) are a type of corticosteroid.
  • DMARDs Disease-modifying anti-rheumatic drugs or “DMARDs” refers to a class of drugs indicated for the treatment of inflammatory arthritides such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, and can also be used in the treatment of other disorders such as the connective tissue diseases systemic sclerosis, systemic lupus erythematosus, and Sjogren syndrome. They can also be used in the treatment of inflammatory myositis, vasculitis, uveitis, inflammatory bowel disease, and in some types of cancer. DMARDS are immunosuppressive or immunomodulatory.
  • DMARDS can be conventional or biologic.
  • 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.
  • ESR erythrocyte sedimentation rate
  • the test measures the rate of fall (sedimentation) of red blood cells (erythrocytes) in a sample of blood placed in a tall vertical tube. Increased ESR indicates inflammation. Results are measured in millimeters of plasma left at the top of the tube after one hour. Results are typically compared to the normal value ranges for persons of the same sex and age, but the normal range values may vary slightly among different laboratories.
  • ferritin refers to serum ferritin, which is ferritin in the blood. Ferritin is a protein that stores iron in cells. Results are typically compared to the normal value ranges for persons of the same sex and age, but the normal range values may vary slightly among different laboratories.
  • Resolution of fever means no temperature >37.5 °C for 48 hours.
  • NSAIDs refers to “non-steroidal anti-inflammatory drugs,” which are commonly used for pain relief and to 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.
  • 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 count of 1 is assigned for any condition that is present at the time of assessment: fever; evanescent rash; pharyngitis; arthritis; myalgia; pleuritis; pericarditis; pneumonitis; lymphadenopathy; hepatomegaly or elevated liver enzymes; leukocyte count > 15,000/pl; ferritin > 3000 pg/1. A total score of >4 is considered to indicate active disease.
  • Systemic-onset juvenile idiopathic arthritis or “systemic juvenile idiopathic arthritis” or “SoJIA” or “SJIA” or “sJIA” refers to a subset of juvenile idiopathic arthritis marked by more severe extra-articular manifestations (fever, cutaneous eruptions). It represents 10-11% of cases of juvenile idiopathic arthritis. Onset usually occurs between 3 and 5 years of age. The clinical signs include fever with oscillating temperatures over a 24-hour period and peaks of over 39°C or more, which are associated with transient cutaneous eruptions and diffuse erythematosus or urticarial-like lesions. Another symptom is arthritis.
  • the number of sites of the body affected by the arthritis vary but affect both the small and large joints in a nearly symmetrical manner. Some patients may also have adenopathy and/or hepatosplenomegaly. Other symptoms such as pericarditis, pleural effusion, or serous peritonitis with abdominal pain may be present. SoJIA patients typically have severe inflammatory disease with a large increase in ferritin levels and a decrease in the percentage of glycosylated ferritin. Physicians often use a “clinical triad” to diagnose this disease: daily fever lasting more than 2 weeks, arthritis, and cutaneous eruptions. See Petty, R et al., J. Rheumatol. 31(2) 390-392 (2004). If the patient does not have cutaneous eruptions, the presence of an adenopathy, hepatosplenomegaly, or serous effusion can also confirm the diagnosis.
  • the anti-IL-18 antibody utilized for therapeutic purposes described herein comprises the CDR sequences and in some embodiments the heavy and light chain variable regions of Antibody 12_GL disclosed in WO 2012/085015, which is incorporated herein by reference in its entirety.
  • Antibody 12_GL is referred to herein as Antibody A.
  • Antibody A is a fully human IgGlK monoclonal antibody (mAb) binding and neutralizing IL- 18.
  • Antibody A inhibits the formation of IL-18/Ra/R[3 active complex in-vitro and in- vivo.
  • Antibody A demonstrates high affinity of 63 pM, which is 6 fold higher compared to IL- 18’ s native inhibitor (IL- 18 binding protein), and reduced Fc binding, to enable efficient antiinflammatory role.
  • IL- 18 binding protein s native inhibitor
  • Fc binding Fc binding
  • Antibody A is expected to demonstrate reduced anti-drug antibodies (ADA).
  • Antibody A demonstrates IL-18 neutralization and bioactivity by reducing IL-18’s effects in various in vitro models with IC50 of sub nanomolar, and has proven efficient in COPD model (NHBE cells infected with Human Rhinovirus (HRV) by inhibiting IFN-y release from PBMCs exposed to infected NHBE media).
  • HRV Human Rhinovirus
  • Antibody A has undergone 13 weeks IV toxicity studies complete with no toxicity up to 100 mg/kg/week.
  • the anti-IL-18 antibody comprises the CDRs of Antibody A: (a) a HCDR1 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 122; (b) a HCDR2 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 123; (c) a HCDR3 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 124; (d) a LCDR1 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 126; (e) a LCDR2 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 127; and (1) a LCDR3 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 128.
  • the anti-IL-18 antibody comprises the Antibody A VH domain (SEQ ID NO: 121) which may be paired with the Antibody A VL domain (SEQ ID NO: 125), so that an antibody antigen-binding site is formed comprising both the Antibody A VH and VL domains.
  • an anti-IL-18 antibody is utilized for both the detection/ diagnostic and therapeutic purposes described herein.
  • 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).
  • the anti-IL-18 antibody useful for therapeutic purposes may comprise the CDR sequences or heavy and light chain variable regions of the antibodies disclosed in WO 2012/085015, which is incorporated herein by reference in its entirety.
  • the antibodies of WO 2012/085015 referred to herein include Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11 GL, and Antibody A.
  • the anti-IL-18 antibody useful for therapeutic purposes may alternatively comprise the CDR sequences of other anti-IL-18 antibodies known in the art (see for example US6706487, WO 2001/058956, EP 1621616, US 2005/0147610; EP 0 974 600; and WO 0158956).
  • the anti-IL-18 antibody may alternatively comprise the CDR sequences or heavy and light chain variable regions of any of the antibodies disclosed in US 8,133,978 B2, which is incorporated herein by reference in its entirety.
  • the antibodies of US 8,133,978 B2 referred to herein include the humanized anti-IL-18 antibodies referred to in claims 1 through 7 of US 8,133,978 B2.
  • the anti-IL-18 antibody of the invention inhibits the binding of IL- 18 to one or both of the IL- 18 receptor (IL-18R, which comprises IL-18Ra/IL- 18R[3) and IL-18BP and thereby reduces IL-18 activity.
  • the anti-IL-18 antibody may bind to an epitope on the IL- 18 molecule which wholly or partially overlaps the IL-18BP binding site.
  • the anti-IL-18 antibody may specifically bind to an epitope of IL-18 which comprises one or more of residues Tyrl, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56, Pro57, Arg58, Gly59, Met60, Argl04, Serl05 and Prol07 of human IL-18 or the corresponding residues from IL- 18 of other species, for example a primate such as Rhesus macaque.
  • a primate such as Rhesus macaque.
  • the anti-IL-18 antibody may bind to an IL- 18 epitope which comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all 17 residues selected from the group consisting of Tyrl, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56, Pro57, Arg58, Gly59, Met60, Argl04, Serl05, and Prol07 of human IL-18.
  • an anti-IL-18 antibody useful in the methods described herein may comprise one or more CDRs as described herein, e.g. a CDR3, and optionally also a CDR1 and CDR2 to form a set of CDRs.
  • the CDR or set of CDRs is a CDR or set of CDRs of any of Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Antibody A, or may be a variant thereof as described herein.
  • HCDR1 may be about 7 amino acids long, comprising or consisting of Kabat residues 31-35b; HCDR2 may be about 16 amino acids long, comprising or consisting of Kabat residues 50-65; HCDR3 may be about 15 amino acids long, comprising or consisting of Kabat residues 95-102; LCDR1 may be about 11 amino acids long, comprising or consisting of Kabat residues 24-34; LCDR2 may be about 7 amino acids long, comprising or consisting of Kabat residues 50-56; and/or LCDR3 may be about 9 amino acids long, comprising or consisting of Kabat residues 89-97.
  • the CDR may include residues 31 to 35 plus an insertion of 2 residues, 35a and 35b.
  • the anti-IL-18 antibody comprises a HCDR1, HCDR2 and/or HCDR3 and/or an LCDR1, LCDR2 and/or LCDR3 as provided in Table 6 (the CDRs belonging to an individual antibody).
  • the anti-IL-18 antibody may comprise a VH as described in any one of the antibodies in the Table 6.
  • it may also comprise a VL of any one of these antibodies.
  • the VL may be from the same or a different antibody as the VH.
  • a VH domain comprising a set of HCDRs of any of the antibodies listed in the Table 6, and/or a VL domain comprising a set of LCDRs of any of the antibodies listed in the Table 6, are also provided herein.
  • the anti-IL-18 antibody comprises Antibody A CDRs with amino acid residue substitutions: (a) aHCDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 122; (b) a HCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 123; (c) aHCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4 or 5 amino acid residue substitutions relative to SEQ ID NO: 124;(d) a LCDR1 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 126; (e) a LCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 127; and (1) a LCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acid residue substitutions relative to SEQ ID NO: 122; (
  • an anti-IL-18 antibody comprises a heavy chain and/or light chain of a parent antibody.
  • the anti -IL-18 antibody comprises any of the antibodies listed in the Table 6 with one or more substitutions within the CDRs.
  • the anti-IL-18 antibody comprises any of the antibodies listed in the Table 6 with one or more substitutions within the VH and/or VL.
  • an antibody molecule of the invention may comprise any one of Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11 GL, and Antibody A, with 17, 16 or 15 or fewer substitutions, e.g. 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 substitutions within the VH and/or VL. Substitutions may potentially be made at any residue, including within the set of CDRs.
  • a VH domain is paired with a VL domain to provide an antibody antigen-binding site, although as discussed above a VH or VL domain alone may be used to bind antigen.
  • the Antibody A VH domain (SEQ ID NO: 121) may be paired with the Antibody A VL domain (SEQ ID NO: 125), so that an antibody antigen-binding site is formed comprising both the Antibody A VH and VL domains.
  • Analogous embodiments are provided for the VH and VL domains of the other antibodies disclosed herein.
  • the Antibody A VH is paired with a VL domain other than that of Antibody A VL. Light-chain promiscuity is well established in the art.
  • VH and VL domains are provided herein.
  • the VH of the parent Antibody 1 or of any of the optimised clones Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11 GL, and Antibody A may be paired with a VL domain from a different antibody e.g.
  • VH and VL domains may be from different antibodies selected from Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11 GL, and Antibody A.
  • an anti-IL-18 antibody comprise a VH domain and a VL domain wherein; (i) the VH domain amino acid sequence is shown in SEQ ID NO: 121 and the VL domain amino acid sequence is shown in SEQ ID NO: 125, (ii) the VH domain amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid substitutions as compared to SEQ ID NO: 121 and the VL domain amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 amino acid substitutions as compared to SEQ ID NO: 125; or (iii) the VH domain amino acid sequence has at least 80%, at least 85%, at least 90% or at least 95% sequence identity with SEQ ID NO: 121 and the VL domain amino acid sequence has at least 80%, at least 85%, at least 90% or at least 95% sequence identity with SEQ ID NO: 125.
  • the anti-IL-18 antibody comprises a VH domain having an amino acid sequence which is at least 90% identical to the full sequence of SEQ ID NO: 121. In some embodiments, the anti -IL-18 antibody comprises a VH domain having an amino acid sequence which is identical to the full sequence of SEQ ID NO: 121. In some embodiments, the anti-IL-18 antibody comprises a VL domain having an amino acid sequence which is at least 90% identical to the full sequence of SEQ ID NO: 125. In some embodiments, the anti-IL-18 antibody comprises a VL domain having an amino acid sequence which is identical to the full sequence of SEQ ID NO: 125.
  • the anti-IL-18 antibody comprises an antibody VH domain and an antibody VL domain, wherein the amino acid sequence of the antibody VH domain and the antibody VL domain are at least 90% identical to the full sequence of SEQ ID NOS: 121 and 125.
  • the anti-IL-18 antibody comprises a heavy chain and light chain comprising the following complementarity determining regions (CDRs): (a) a HCDR1 comprising the amino acids of SEQ ID NO: 129; (b) a HCDR2 comprising the amino acids of SEQ ID NO: 130; (c) a HCDR3 comprising the amino acids of SEQ ID NO: 131; (d) a LCDR1 comprising the amino acids of SEQ ID NO: 132; (e) a LCDR2 comprising the amino acids of SEQ ID NO: 133; and (I) a LCDR3 comprising the amino acids of SEQ ID NO: 134.
  • CDRs complementarity determining regions
  • the anti-IL-18 antibody of the invention comprises: a heavy chain and light chain comprising the following complementarity determining regions (CDRs): (a) a HCDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 129; (b) a HCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 130; (c) aHCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4 or 5 amino acid residue substitutions relative to SEQ ID NO: 131; (d) a LCDR1 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 132; (e) a LCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 133; and (I) a LCDR3 having an amino acid sequence identical to or comprising 1, 2,
  • CDRs complementarity
  • the IL-18 antibody comprises a heavy chain having an amino acid sequence identical to or comprising 1 to 12 amino acid residue substitutions relative to a heavy chain selected from the group consisting of: SEQ ID NO: 137, SEQ ID NO: 145, and SEQ ID NO: 149; and a light chain having an amino acid sequence identical to or comprising 1 to 12 amino acid residue substitutions relative to a light chain selected from the group consisting of: SEQ ID NO: 141 and SEQ ID NO: 157.
  • the anti-IL-18 antibody further comprises substituting the residue at position 71 of the light chain with the corresponding residue found in a donor antibody from which the CDRs are derived.
  • the anti-IL-18 antibody comprises a tyrosine at position 71 of the light chain.
  • the anti-IL-18 antibody comprises a phenylalanine at position 71 of the light chain.
  • the anti-IL-18 antibody comprises aheavy 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.
  • the anti-IL-18 antibody comprises aheavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 153. In one embodiment, the anti-IL- 18 antibody the anti-IL-18 antibody comprises aheavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 153. In one embodiment, the anti-IL-18 antibody the anti-IL-18 antibody comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 153.
  • the anti-IL-18 antibody may lack antibody constant regions, for example a scFv.
  • anti-IL-18 antibody may comprise an antibody constant region.
  • the anti-IL-18 antibody may be a whole antibody such as an IgG, i.e. an IgGl, IgG2, or IgG4, or may be an antibody fragment or derivative as described below.
  • Antibody molecules can also have other formats, e.g. IgGl with YTE (Dall’Acqua et al. (2002) J. Immunology, 169: 5171-5180; Dall’Acqua et al. (2006) J Biol. Chem. 281(33):23514-24) and/or TM mutations (Oganesyan et al. (2008) Acta Cryst D64:700-4) in Fc region.
  • Another aspect of the invention provides an anti-IL-18 antibody comprising an antibody antigen binding site or antibody molecule as described herein which competes for binding to IL- 18 with any antibody molecule which: (i) binds IL- 18 and (ii) comprises an antibody molecule, VH and/or VL domain, CDR e.g. HCDR3, and/or set of CDRs listed in the Table 6.
  • the anti-IL-18 antibody may compete with an antibody molecule comprising: (i) a VH domain having the sequence of SEQ ID NO: 152 and a VL domain having the sequence of SEQ ID NO: 157; (ii) a VH domain having a sequence with 15 or fewer amino acid substitutions such as 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 as compared to SEQ ID NO: 152; and a VL domain having a sequence with 13 or fewer amino acid substitutions such as 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 as compared to or SEQ ID NO: 157, or; (iii) a VH domain and a VL domain having sequences with at least 90% sequence identity to SEQ ID NO: 152 and SEQ ID NO: 157, respectively.
  • Competition between anti-IL-18 antibodies may be assayed easily in vitro, for example using ELISA and/or by a biochemical competition assay such as one tagging a specific reporter molecule to one anti-IL-18 antibody which can be detected in the presence of one or more other untagged anti-IL-18 antibodies, to enable identification of anti-IL-18 antibodies which bind the same epitope or an overlapping epitope.
  • a biochemical competition assay such as one tagging a specific reporter molecule to one anti-IL-18 antibody which can be detected in the presence of one or more other untagged anti-IL-18 antibodies, to enable identification of anti-IL-18 antibodies which bind the same epitope or an overlapping epitope.
  • VH and VL domains whose sequences are specifically disclosed herein may be employed in accordance with the present invention.
  • aspects of the invention provide an anti-IL-18 antibody, comprising a VH domain that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with a VH domain of any of the antibodies listed herein, for which VH domain sequences are shown in the appended Table 6 below; and/or comprising a VL domain that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with a VL domain of any of the antibodies listed herein, for which VL domain sequences are shown in the appended Table 6 below.
  • an anti -IL-18 antibody comprising a VH domain having a set of VH CDRs that have at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with the set of VH CDRs of any of the antibodies listed herein, for which VH CDR sequences are shown in the appended Table 6; and/or comprising a VL domain having a set of VL CDRs that have at that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with the set of VL CDRs of any of the antibodies listed herein, for which the VL CDR sequences are shown in the appended Table 6.
  • Algorithms that can be used to calculate % identity of two amino acid sequences are known in the art and include e.g. BLAST [Altschul et al. (1990) J. Mol. Biol. 215: 405-410], FASTA [Pearson and Lipman (1988) PNAS USA 85: 2444-2448], or the Smith-Waterman algorithm [Smith and Waterman (1981) J. Mol Biol. 147: 195-197] e.g. employing default parameters.
  • compositions comprising anti-IL-18 antibodies are provided in formulations with a wide variety of pharmaceutically acceptable carriers (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)).
  • Various pharmaceutically acceptable carriers which include vehicles, adjuvants, and diluents, are available.
  • Nonlimiting exemplary carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
  • compositions comprising anti-IL-18 antibodies may be formulated for injection or infusion, by dissolving, suspending, or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids, or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • the compositions may be formulated for inhalation, for example, using pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • compositions may also be formulated, in various embodiments, into sustained release microcapsules, such as with biodegradable or non-biodegradable polymers.
  • a non-limiting exemplary biodegradable formulation includes poly lactic acid-glycolic acid polymer.
  • a non-limiting exemplary non-biodegradable formulation includes a polyglycerin fatty acid ester. Certain methods of making such formulations are described, for example, in EP 1 125 584 Al.
  • compositions contained in the unit dosage may comprise saline, sucrose, or the like; a buffer, such as phosphate, or the like; and/or be formulated within a stable and effective pH range.
  • the composition may be provided as a lyophilized powder that may be reconstituted upon addition of an appropriate liquid, for example, sterile water.
  • the composition comprises one or more substances that inhibit protein aggregation, including, but not limited to, sucrose and arginine.
  • a composition of the invention comprises heparin and/or a proteoglycan.
  • a method of treating subjects having adult-onset Still’s disease (AOSD) or systemic-onset juvenile idiopathic arthritis (SoJIA) comprising administering an effective amount of an anti-IL-18 antibody to a human subject diagnosed with AOSD or SoJIA.
  • AOSD adult-onset Still’s disease
  • SoJIA systemic-onset juvenile idiopathic arthritis
  • the subject is diagnosed with AOSD based on having 5 or more of the following criteria, 2 of which are major:
  • the subject has reported a recurring fever >38°C within the last 5 days of screening and baseline visits.
  • the subject is on a stable dose for at least 48 hours prior to a baseline visit. In some embodiments, if the subject is undergoing treatment with glucocorticoids, the subject is on a stable dose for at least 48 hours prior to a baseline visit. In some embodiments, if the subject is undergoing treatment with conventional DMARDs, the subject is on a stable dose for at least 12 weeks prior to a baseline visit.
  • the subject if the subject has received treatment with biological DMARDs, the subject has undergone the required washout period prior to a baseline visit, and the required washout period is as follows: anakinra - 1 week; etanercept, rilonacept - 4 weeks; adalimumab, certolizumab, infliximab, golimumab, abatacept, tocilizumab and canakinumab - 8 weeks; and rituximab - 36 weeks.
  • the subject does not have a serum creatinine concentration of > 1.5 mg/dl. In some embodiments, the subject does not have hemoglobin ⁇ 10 g/dl, neutrophils ⁇ l,500/pl and/or thrombocytes ⁇ 75,000/pl.
  • the method comprises a method of treating SoJIA.
  • the subject has elevated free or total serum IL-18 levels.
  • the level of serum IL- 18 is measured prior to administration of the anti-IL- 18 antibody.
  • the level of serum IL- 18 is measured after administration of the anti-IL-18 antibody.
  • the level of serum IL-18 is measured as a marker for effectiveness of treatment.
  • the level of serum IL- 18 is elevated as compared to levels in a subject without AOSD or SoJIA or as compared to a negative control.
  • the levels of serum IL- 18 in the subject are measured after administration of the anti-IL-18 antibody as a marker for effectiveness of treatment.
  • 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. [00101] In some embodiments, the anti-IL-18 antibody is administered in the form of a pharmaceutically acceptable composition.
  • the anti-IL-18 antibody is administered for a period of 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.
  • the anti-IL-18 antibody is administered once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
  • the subject achieves resolution of fever.
  • the subject achieves a reduction of CRP. In some embodiments, the subject achieves a reduction of CRP of >50% from baseline to week 4. In some embodiments, the subject achieves a reduction of CRP of >50% from baseline to week 12.
  • the subject achieves a reduction of serum IL-18 levels. In some embodiments, the subject achieves a reduction of serum total IL-18 levels. In some embodiments, the subject achieves a reduction of serum free IL-18 levels. In some embodiments, the subject has undetectable levels of serum IL-18 at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum IL- 18 at about 12 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum total IL- 18 at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum total IL- 18 at about 12 weeks after administration of the anti-IL-18 antibody.
  • the subject has undetectable levels of serum free IL-18 at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject has undetectable levels of serum free IL- 18 at about 12 weeks after administration of the anti-IL-18 antibody.
  • the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA as measured by the Physician and/or Patient Global Assessment of disease activity assessed on a Visual Analogue Scale (VAS). In some embodiments, the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA as measured by the Physician and/or Patient Global Assessment of disease activity assessed on a Visual Analogue Scale (VAS) at least at about 4 weeks after administration of the anti-IL-18 antibody.
  • VAS Visual Analogue Scale
  • the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA as measured by the Physician and/or Patient Global Assessment of disease activity assessed on a Visual Analogue Scale (VAS) at least at about 12 weeks after administration of the anti-IL-18 antibody.
  • VAS Visual Analogue Scale
  • the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the modified Pouchot score. In some embodiments, the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the modified Pouchot score at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the modified Pouchot score at about 12 weeks after administration of the anti-IL- 18 antibody.
  • the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the DAS28-CRP score. In some embodiments, the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the DAS28- CRP score at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject exhibits a reduction of the signs and symptoms of AOSD or SoJIA assessed using the DAS28-CRP score at about 12 weeks after administration of the anti-IL-18 antibody.
  • the subject experiences a reduction in serum ferritin. In some embodiments, the subject experiences a reduction in serum ferritin at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject experiences a reduction in serum ferritin at about 12 weeks after administration of the anti-IL-18 antibody.
  • the subject experiences a reduction in erythrocyte sedimentation rate (ESR). In some embodiments, the subject experiences a reduction in erythrocyte sedimentation rate (ESR) at about 4 weeks after administration of the anti-IL-18 antibody. In some embodiments, the subject experiences a reduction in erythrocyte sedimentation rate (ESR) at about 12 weeks after administration of the anti-IL-18 antibody.
  • ESR erythrocyte sedimentation rate
  • the subject is administered one or more additional therapeutically active agents.
  • the one or more additional therapeutically active agents comprise at least one of non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, systemic glucocorticoids, and conventional synthetic disease-modifying antirheumatic drugs (DMARDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • corticosteroids corticosteroids
  • systemic glucocorticoids systemic glucocorticoids
  • DMARDs conventional synthetic disease-modifying antirheumatic drugs
  • the conventional synthetic diseasemodifying anti-rheumatic drug (DMARD) is methotrexate.
  • the corticosteroid is prednisone.
  • kits for the detection and/or treatment of a condition associated with elevated IL-18 including AOSD or SoJIA.
  • the kit may contain an antibody, one or more non-naturally occurring detectable labels, marker, or reporter, a pharmaceutically acceptable carrier, a physiologically acceptable carrier, instructions for use, a container, a vessel for administration, an assay substrate, or any combination thereof.
  • the kit is for use in a method of detecting IL-18 in a biological sample. It may contain an anti -IL- 18 antibody and reagents for carrying out the method.
  • the kit is for use in a method of detecting IL-18 in a biological sample from a subject having or suspected of having AOSD or SoJIA. It may contain an anti-IL-18 antibody and reagents for carrying out the method.
  • the kit is for use in method of detecting elevated IL-18 in a biological sample from a subject, optionally wherein the subject is suspected of AOSD or SoJIA and also for treating the subject after diagnosis by administering an anti-IL-18 antibody in an effective amount. It may contain an anti-IL-18 antibody and reagents for carrying out the method.
  • the kit for use in a method of detecting and/or treating comprises a solid phase to which the anti-IL-18 antibody reagent is attached. In some embodiments, the kit for use in a method of detecting and/or treating comprises a solid phase to which IL- 18 derived from the biological sample will be attached.
  • the solid phase to be used in the kits of the present invention includes, but is not limited, to microplates, magnetic particles, filter papers for immunochromatography, polymers such as polystyrene, glass beads, glass filters and other insoluble carriers.
  • a solid substrate containing many compartments or regions has at least one compartment coated with antibodies of the invention.
  • kits of the invention may also include a further component to the diagnostic agent, the anti-IL-18 antibody.
  • the further component may include, but is not limited to, reagents, enzymes for labeling, substrates therefor, radioisotopes, light-reflecting substances, fluorescent substances, colored substances, buffer solutions, and plates, and those mentioned herein above.
  • Antibody A refers to an anti-IL-18 antibody, wherein the anti-IL-18 antibody comprises the following six CDRs: a heavy chain CDR having an amino acid sequence of SEQ ID NO: 122; a heavy chain CDR having an amino acid sequence of SEQ ID NO: 123; a heavy chain CDR having an amino acid sequence of SEQ ID NO: 124; a light chain CDR having an amino acid sequence of SEQ ID NO: 126; a light chain CDR having an amino acid sequence of SEQ ID NO: 127; and a light chain CDR having an amino acid sequence of SEQ ID NO: 128.
  • Antibody A has a variable heavy chain (VH) having an amino acid sequence of SEQ ID NO: 121 and a variable light chain (VL) having an amino acid sequence of SEQ ID NO: 125.
  • Example 1 A Phase lb, 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
  • 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. It is the first time Antibody A will be studied in subjects with AOSD. Initially, 6 subjects were enrolled at the 7 mg/kg dose. If this dose was found to be tolerable in the first 6 subjects by the Safety Review Committee, the dose would be increased to 14 mg/kg (maximum 1000 mg) in the next set of 6 subjects. Per the predefined algorithm, the Safety Review Committee was given the option to decide to expand the number of subjects in the first cohort before proceeding with the dose escalation in the second cohort of subjects. If the safety of Antibody A at 7 mg/kg dose was not acceptable, dosing would be decreased to a dose of 4 mg/kg (maximum 300 mg) per the predefined algorithm.
  • the secondary objectives of the study are: to evaluate the effect of Antibody A on the systemic clinical manifestations of AOSD; to measure the effect of Antibody A on the systemic markers of inflammation in subjects with AOSD; and to assess the PK of Antibody A in subjects with AOSD.
  • the exploratory objectives are to assess the PD of Antibody A in subjects with AOSD and to assess the immunogenicity of Antibody A in subjects with AOSD.
  • the primary endpoint of the study is incidences of AEs, and changes in vital signs and clinical laboratory results.
  • the secondary endpoints of the study are: proportion of subjects who achieved resolution of fever, defined as no temperature > 37.5°C for 48 hours; proportion of subjects whose CRP reduced >50% from Baseline to Week 4 and Week 12; change from baseline to Week 4 and Week 12 in the Physician and Patient Global Assessment of disease activity assessed on a VAS from no evidence of disease (0 mm) to very severe disease activity (100 mm); change from baseline to Week 4 and Week 12 in the modified Pouchot score; change from baseline to Week 4 and Week 12 in the DAS28-CRP; change from baseline to Week 4 and Week 12 in CRP, ferritin, and ESR; and serum concentrations of Antibody A over time.
  • Subject is 18 to 75 years of age (inclusive) at the time of consent.
  • the date of signature of the informed consent is defined as the beginning of the Screening Period. This inclusion criterion will only be assessed at the Screening Visit (Visit 1).
  • Subject has been diagnosed with AOSD based on classification criteria (according to Yamaguchi et al. (1992) J Rheumatol. 19(3): 424-430) defined as having 5 or more of the following criteria, 2 of which are major: a. Major Criteria i. Fever >39°C, lasting 1 week or longer ii. Arthralgia or arthritis, lasting 2 weeks or longer iii. Typical rash iv. Leukocytes >10,000 mm 3 with >80% polymorphonuclear cells b. Minor Criteria i. Sore throat ii. Recent development of significant lymphadenopathy iii. Hepatomegaly or splenomegaly iv. Abnormal liver function tests v. Negative tests for antinuclear antibody (IF) and rheumatoid factor (IgM)
  • Subject has reported a recurring fever >38°C, consistent with active disease, within the last 5 days of the Screening and Baseline visits.
  • washout (normalization) period for subjects who have received treatment with biological DMARDs, subject has the required washout (normalization) period prior to the Baseline Visit (Visit 2).
  • the washout (normalization) period for biological DMARDs is 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
  • a highly effective method of birth control is defined as one that results in a low failure rate (ie, ⁇ 1% per year) when used consistently and correctly, such as oral/injectable/inserted/implanted/transdermal contraceptives, condom with diaphragm, condom with spermicide, diaphragm with spermicide, intrauterine hormone-releasing system or intrauterine device (IUD), or sexual abstinence.
  • Contraception is not required where at least 6 weeks have passed since sterilization, defined as females having undergone one of the following surgeries: hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy; and males who are vasectomized. Contraception is not required where females are postmenopausal (12 consecutive months of spontaneous amenorrhea and age >51 years).
  • Subject has a chronic severe or uncontrolled medical disorder that might confound the results of safety assessments conducted in the study.
  • Subject has a relevant, active infection or another disease, which entails a tendency towards infection.
  • Subject has active macrophage activation syndrome.
  • Subject has a history of unresolved latent tuberculosis.
  • Subject has the following abnormal values: a. Serum creatinine concentration >1.5 mg/dl. b. Hemoglobin ⁇ 10 g/dl, neutrophils ⁇ 1 ,500/pl and/or thrombocytes ⁇ 75,000/pl.
  • Subject has a history of neoplasia with the exception of a curatively treated nonmelanoma skin tumor or carcinoma of the cervix treated in situ without any indication of recurrence within the last 10 years.
  • Subject has received a vaccination with a live vaccine within 12 weeks prior to the Baseline Visit (Visit 2).
  • Subject has used an investigational product or been enrolled in a clinical study including vaccines within 30 days of the Screening Visit (Visit 1).
  • Subject has known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any ingredients of the investigational product.
  • Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study with the prior approval of the Medical Monitor.
  • the first screening visit will be entered into the electronic case report form (eCRF) as the Screening Visit and the repeat assessments entered into the eCRF as an unscheduled visit.
  • eCRF electronic case report form
  • Subjects can decline to continue receiving study drug at any time during the study. If this occurs, the investigator is to discuss with the subject the completion of the Followup / Early Termination Visit 4 weeks following the last dose of study drug.
  • the investigator also has the right to withdraw subjects from the study at any time for any reason. If a subject is withdrawn before completing the study, the subject should be followed-up as instructed in the Schedule of Assessments (Table 1). The reason for withdrawal must be determined by the investigator and recorded in the subject’s medical record and in the electronic case report form (eCRF). If a subject is withdrawn for more than 1 reason, each reason should be documented in the source document and the most clinically relevant reason should be entered in the eCRF.
  • DMARDs a.
  • DMARDs normalization (washout) period for biological DMARDs prior to the Baseline Visit (Visit 2).
  • the normalization period for DMARDs is as follows: Anakinra - 1 week; Etanercept, rilonacept - 4 weeks; Adalimumab, certolizumab, infliximab, golimumab, abatacept, tocilizumab, canakinumab - 8 weeks; Rituximab - 36 weeks.
  • Re-consent is required if the 28-day Screening or Re-screening periods have lapsed.
  • d. Includes pulse, blood pressure, respiratory rate, body temperature, and body weight. Body temperature will be measured by the subject
  • Urinalysis to include pH, specific gravity, dipstick determinations of protein, blood, glucose and ketones; microscopic if blood or protein 2+ or higher.
  • l For females of childbearing potential. A subject is not considered to be of childbearing potential if she is postmenopausal (12 consecutive months of spontaneous amenorrhea and age >51 years); surgically sterile (having undergone one of the following surgeries: hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy); and at where at least 6 weeks has passed since sterilization. Positive urine pregnancy test results should have a local serum pregnancy test performed as confirmation.
  • Subjects should be observed for signs and symptoms of hypersensitive or allergic reactions, with monitoring of vital signs as needed, from administration of Antibody A through the 2-hour post-dose PK sample collection. o. Subjects who withdraw from the study less than 28 days from the last dose, and who decline to return to the site for the early termination visit, may have relevant early termination procedures listed in the eCRF performed via a Safety Follow-up Telephone Call.
  • ADA anti-drug antibody
  • CRP C-reactive protein
  • DAS28-CRP Disease Activity Score-28 for rheumatoid arthritis with CRP
  • DMARD disease-modifying anti-rheumatic drugs
  • ECG electrocardiogram
  • ESR erythrocyte sedimentation rate
  • IL- 18 interleukin- 18;
  • IL-18BP interleukin- 18 binding protein
  • PK pharmacokinetic
  • VAS Visual Analog Scale.
  • Antibody A is the investigational product that will be and was used in this study. It was in the form of lyophilized powder in a single-use glass vial. The dose was 7 mg/kg (maximum 500 mg) for the first cohort of 6 subjects, and a predefined algorithm will determine the dosing of the second cohort of 6 subjects. The frequency of dosing was and is once every 4 weeks during the treatment period. The mode of administration was and is intravenous.
  • Antibody A will be and was administered at a dose of 7 mg/kg (maximum 500 mg) IV every 4 weeks to the first cohort of 6 subjects. Safety will be and was assessed by an SRC for these 6 subjects. Twenty-eight days after the first cohort’s 6th subject has completed his/her first dose of Antibody A, if the safety is acceptable per a predefined algorithm, the second cohort of 6 subjects will be dosed with 14 mg/kg (maximum 1000 mg) IV. Per the predefined algorithm, the SRC may decide to expand the number of subjects in the first cohort before proceeding with the dose escalation in the second cohort of subjects. If the safety of 7 mg/kg is not acceptable, dosing will be decreased to 4 mg/kg (maximum 300 mg) per the predefined algorithm.
  • Antibody A will be and was administered via a slow IV infusion (over a minimum of 60 minutes) to reduce the risk of infusion reactions.
  • Appropriate drugs and medical equipment to treat acute anaphylactic must be immediately available, and study personnel must be trained to recognize and treat anaphylaxis.
  • Subjects should be observed for signs and symptoms of hypersensitive or allergic reactions, with monitoring of vital signs as needed, from administration of Antibody A through the 2-hour post-dose PK sample collection.
  • Antibody A will be and was administered at a dose of 7 mg/kg (500 mg maximum) IV every 4 weeks to the first cohort of 6 subjects. Based on the review by the Safety Review Committee, if the safety is acceptable per a predefined algorithm, the second cohort of 6 subjects will be dosed with 14 mg/kg (maximum 1000 mg) IV. Per the predefined algorithm, the SRC may decide to expand the number of subjects in the first cohort before proceeding with the dose escalation in the second cohort of subjects. If not acceptable, dosing will be decreased to 4 mg/kg (maximum 300 mg) per the predefined algorithm.
  • Prior therapies includes all treatments received within 28 days of the date of first dose of investigational product.
  • Concomitant therapies refer to all therapies taken from Screening and for 4 weeks after the last dose of study drug or last visit, whichever is later. Concomitant therapy information must be recorded on the appropriate eCRF page.
  • Patients are treated for all intercurrent medical conditions at the discretion of the investigator in accordance with community standards of medical care. Subjects receive treatments for palliation of symptoms associated with AOSD.
  • Subjects must meet the 48-hour stable dose requirement prior to the Baseline Visit (Visit 2) if a subject is undergoing treatment with NSAIDs and/or glucocorticoids.
  • Subjects must meet the required normalization (washout) period for biological DMARDs prior to the Baseline Visit (Visit 2).
  • the normalization period for DMARDs 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).
  • Any new therapy, other than Antibody A, designed to treat the subject’s AOSD is prohibited during the study. This includes biologies (eg, anti-IL-1, anti-IL-6, anti-TNFa) as well as the initiation or increase of any glucocorticoid treatment. [00155] During the study, new initiation of investigational compounds is prohibited.
  • Vaccines that are considered by the investigator during the clinical trial should be discussed with the medical monitor prior to administration.
  • the sequence and maximum duration of the study periods will be as follows.
  • the screening period will be up to 28 days.
  • the treatment period will be 8 weeks.
  • the follow-up period will be 4 weeks after the last dose of the investigational product or last visit, whichever is later.
  • the maximum study duration for each subject is up to 16 weeks.
  • the maximum treatment duration for each subject is 8 weeks.
  • Safety and tolerability assessments will include the frequency and severity of AEs as well as the evaluation of changes in clinical laboratory values and vital signs.
  • Hematology tests include Hemoglobin, hematocrit, platelet count (or estimate), and white blood cell count including differential.
  • Serum chemistry tests 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.
  • a serum/urine pregnancy test will be administered for females of childbearing potential.
  • Urinalysis tests include pH, specific gravity, dipstick determinations of protein, blood, glucose and ketones; and microscopic if blood or protein 2+ or higher.
  • Laboratory specimens will be collected and shipped to a central laboratory facility for processing by the appropriate laboratory.
  • Local laboratory results creatinine, hemoglobin, neutrophils, thrombocytes, and serum pregnancy
  • central laboratory specimens must also be collected as part of the screening procedures.
  • the total collected volume may be less than the above in cases where the Baseline visit occurs with 48 hours of the Screening visit.
  • CRP C-reactive protein
  • ESR erythrocyte sedimentation rate
  • IL- 18 interleukin- 18
  • IL-18BP interleukin 18 binding protein.
  • a laboratory value is out of the reference range, it is not necessarily clinically relevant.
  • the investigator must evaluate the out-of-range values and record his/her assessment of the clinical relevance in the subject’s source documentation.
  • Abnormal laboratory values may be considered AEs if they are clinically significant, if they require an intervention, or if they change the administration of study drug.
  • Blood pressure, pulse rate, respiratory rate, temperature, and body weight will be measured at times specified in the Schedule of Assessments (Table 1). Additional blood pressure and pulse rate measurements may be performed, as determined by the investigator, to ensure appropriate monitoring of subject safety and accurate recording of vital sign measurements. Any changes from baseline which are deemed clinically significant by the investigator are to be recorded as an AE and followed.
  • a standard 12-lead ECG will be performed after the subject has been supine for approximately 5 minutes. All ECG recordings will be identified with the subject number, date, and time of the recording and a copy will be included with the subject’s source documentation.
  • ECGs Twelve-lead ECGs will be performed locally at Baseline and then as required (Table 1). All ECG values which, in the investigator’s opinion, show clinically relevant or pathological changes during or after termination of the treatment are to be discussed with the Medical Monitor and reported as AEs and followed.
  • the investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE described previously. At each visit, the subject will be allowed time to spontaneously report any issues since the last visit or evaluation.
  • Antibody A The efficacy of Antibody A will be determined by fever resolution, CRP, ferritin, ESR, Physician and Patient Global Assessments using VAS, modified Pouchot score, and DAS28CRP.
  • Fever resolution will be determined by measuring body temperature at study visits and collecting subject reports of fevers experienced within the last 5 days prior to the Screening and Baseline Visits, and within the last 48 hours at subsequent visits.
  • Body temperature, CRP, ferritin, and ESR will be measured at the times specified in the Schedule of Assessments (Table 1).
  • the Patient Global Assessment of Disease Activity (PtGA) will be measured at the times specified in the Schedule of Assessments (Table 1), using 100 mm VAS ranging from no evidence of disease (0 mm) to very severe disease activity (100 mm).
  • the Physician Global Assessment of Disease Activity will be measured at the times specified in the Schedule of Assessments (Table 1), using 100 mm VAS ranging from no evidence of disease (0 mm) to very severe disease activity (100 mm). To enhance objectivity, the physician must not be aware of the specific PtGA, when performing his/her own assessment on that patient.
  • the modified Pouchot score will be measured at the times specified in the Schedule of Assessments (Table 1). For each of the 12 clinical conditions listed, a score count of 1 is assigned for any that are present at the time of assessment (Rau et al. (2010) J Rheumatol. 37(1 l):2369-2376): fever; evanescent rash; pharyngitis; arthritis; myalgia; pleuritis; pericarditis; pneumonitis; lymphadenopathy; hepatomegaly or elevated liver enzymes; Leukocyte count > 15,000/pl; Ferritin > 3000 pg/1. A total score of > 4 is considered to indicate active disease.
  • DAS28-CRP will be measured at the times specified in the Schedule of Assessments (Table 1). To calculate the DAS28-CRP, information about the following disease variables will be collected: the number of swollen joints and tender joints using 28-joint count (TJC28 and SJC28); PtGA measured on a VAS of 100 mm; and CRP measured in mg/L.
  • the DAS28 score ranges from 0 to 10, with higher scores indicating a more severe current activity of the disease.
  • the DAS28 score will also be categorized into disease activity states according to the cut-off values provided in Table 3.
  • PD will be measured by levels of IL-18 and IL-18BP, obtained at various time points during study participation (Table 1).
  • An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with the product.
  • An AE can therefore be any unfavorable and unintended sign (including a new, clinically important abnormal laboratory finding), symptom, or disease, temporally associated with the product, whether or not related to the product.
  • An AE will be considered treatment-emergent if it occurs after the first dose of investigational product (including the duration of infusion) and within 28 days of a subject’s last dose of investigational product.
  • All AEs are collected from the time the informed consent is signed through the follow-up period (Table 1). This includes events occurring during the screening phase of the study, regardless of whether investigational product is administered. Where possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, then each symptom should be listed individually. All AEs should be captured on the appropriate AE pages in the eCRF and in source documents.
  • AE that changes in severity over time should be recorded in the eCRF once at the highest severity with two exceptions.
  • the first exception is worsening of non-AOSD related pretreatment events after initiation of investigational product must be recorded as new AEs.
  • the subject experiences mild, intermittent headaches prior to dosing with investigational product; however, the headache intensity increases to moderate after the first dose of investigational product, a new AE of moderate intermittent headaches is to be recorded in the source documents and eCRF.
  • the second exception is an AE which begins as a non-serious event, which later meets the definition of an SAE, should be entered once for the non-serious portion of the AE, and then be re-recorded as a new event with the start date the day it became serious.
  • Grade 1 is defined as Mild; asymptomatic or mild symptoms; or clinical or diagnostic observations only; or intervention not indicated.
  • Grade 2 is defined as Moderate; or minimal, local or non-invasive intervention indicated; or limiting age- appropriate instrumental activities of daily living (ADL).
  • Grade 3 is defined as Severe or medically significant but not immediately life-threatening; or hospitalization or prolongation of hospitalization indicated; or disabling; or limiting self-care ADL.
  • Grade 4 is defined as Lifethreatening consequences; or urgent intervention indicated.
  • Grade 5 is death related to AE.
  • a physician investigator must make the assessment of relationship to investigational product for each AE. The investigator should decide whether, in his or her medical judgment, there is a reasonable possibility that the event may have been caused by the investigational product. If there is no valid reason for suggesting a relationship, then the AE should be classified as “not related”. Otherwise, the AE should be categorized per the guidelines below. The causality assessment must be documented in the source document and the eCRF (Table 4).
  • An SAE is any untoward medical occurrence, whether considered to be related to investigational product or not, that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly; or is an important medical event.
  • inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay.
  • An elective hospital admission to treat a condition present before exposure to the test drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or event as an SAE.
  • an overnight stay in the hospital that is only due to transportation, organization, or accommodation problems and without medical background does not need to be considered an SAE.
  • the onset date of the SAE is defined as the date the event meets serious criteria.
  • the resolution date is the date an outcome is reached, stabilization is achieved (ie, the investigator does not expect any further improvement or worsening of the event), or the event is otherwise explained.
  • Fatal should only be designated as an outcome when the AE results in death. If more than 1 AE is possibly related to the subject’s death, the outcome of death should be indicated for each such AE.
  • Any AE that results in the subject’s death must have fatal checked as an outcome with the date of death recorded as the resolution date. AEs resulting in death must be reported within 24 hours as a SAE, if not already reported as such.
  • a highly effective method of birth control is defined as one that results in a low failure rate (ie, ⁇ 1% per year) when used consistently and correctly, such as oral/injectable/inserted/implanted/ transdermal contraceptives, condom with diaphragm, condom with spermicide, diaphragm with spermicide, intrauterine hormone-releasing system or intrauterine device (IUD), or sexual abstinence.
  • Contraception is not required where at least 6 weeks have passed since sterilization, defined as females having undergone one of the following surgeries: hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy; and males who are vasectomized. Contraception is not required where females are postmenopausal (12 consecutive months of spontaneous amenorrhea and age >51 years).
  • Females and males with female partners should be instructed to contact the investigator or study staff immediately if pregnancy occurs or is suspected.
  • Pregnancy testing will be conducted on every female as per the schedule of assessments (Table 1). A female who is found to be pregnant at Screening will be excluded from the study and considered to be a screening failure. A female who is found to be pregnant after receiving investigational product is required to be discontinued from the study and the end of study visit assessments performed as soon as possible after learning of the pregnancy.
  • the investigator must report the pregnancy of any female (study participant or female partner of male study participant) who becomes pregnant during investigational product treatment or within 28 days of discontinuing the investigational product (permission must be obtained from the pregnant female partner of a male patient to follow the pregnancy to conclusion and report the results).
  • the pregnancy must be reported within 24 hours of learning of the pregnancy to the CRO using the Pregnancy Data Collection Form via the same fax and email address as for SAE reporting.
  • the investigator should contact the designated individual(s) who receive pregnancy notification and record information related to the pregnancy on the Pregnancy Form/other designated form provided by the Sponsor or its designee.
  • the investigator is also responsible for following the pregnancy until delivery or termination. These findings must be reported on the Pregnancy Data Collection Form and forwarded to the designated individual(s). The event meets the SAE criterion only if it results in a spontaneous abortion or a congenital anomaly.
  • the Sponsor or its designee is responsible for notifying the relevant regulatory authorities and if applicable, US central institutional review board (IRB) of related, unexpected SAEs.
  • IRS US central institutional review board
  • the Sponsor or its designee is responsible for notifying active sites of all related, unexpected SAEs occurring during all interventional studies across the development program.
  • the investigator is responsible for notifying the local IRB, local ethics committee (EC), or the relevant local regulatory authority of all SAEs that occur at his/her site, as required.
  • EC local ethics committee
  • Overdose or medication error of investigational product defined below (Table 5), must be reported to the Sponsor using the SAE reporting procedures outlined above whether or not they result in an AE/SAE.
  • the 24-hour reporting period for SAEs does not apply to overdose or medication error event(s) unless the overdose or medication error event results in an SAE.
  • Table 5 Definition of Overdose and Medication Error
  • Missing doses are not considered a medication error event and do not need reporting. Note that an overdose or medication error event can meet one or both of the above categories.
  • a Safety Review Committee (SRC) will be involved in the conduct of this study.
  • the SRC will be comprised of representatives from the Sponsor and the study sites, including 1 medically qualified member from each participating site.
  • the SRC has the responsibility for monitoring the clinical study’s progress and the safety of the participating subjects.
  • the second cohort of 6 subjects will be dosed at 4 mg/kg (maximum 300 mg) IV at Baseline, Week 4, and Week 8.
  • the SRC will assess the safety information and determine whether to expand the number of subjects in the first cohort or to proceed with the dose escalation in the second cohort of subjects.
  • the SRC will determine whether to proceed with the dose escalation in the second cohort of 6 subjects.
  • the escalated dose regimen will be 14 mg/kg (maximum 1000 mg) IV at Baseline, Week 4, and Week 8.
  • the SRC will assess the safety information and determine whether to continue the subjects at 14 mg/kg (maximum 1000 mg) dose or to drop down to the prior 7 mg/kg (500 mg maximum) dose.
  • the second cohort experiences > 1 SAE atributed to Antibody A subjects will be dropped down to the prior 7 mg/kg (500 mg maximum) dose.
  • the Enrolled Population includes all subjects who are enrolled; and the Safety Population includes all subjects who are enrolled and receive at least one treatment administration during this trial.
  • SAP Statistical Analysis Plan
  • 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 who have both a baseline value and corresponding value at the time point 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 frequency and percentage. Where appropriate, descriptive statistics may be presented with 95% confidence intervals. All descriptive summaries will be produced by Antibody A dose level and will include an overall category.
  • Protocol deviations All subject data will be reviewed for the occurrence of protocol deviations. Prior to database lock, all protocol deviations will be reviewed and classified with respect to the potential to influence experimental outcomes.
  • Demographic variables include age, gender, race, ethnicity, height, weight, and body mass index.
  • Exposure to investigational product will be summarized by dose level using descriptive statistics. Subjects will be summarized according to cumulative exposure.
  • Safety analyses will be conducted using data from the Safety Population. Safety variables include TEAEs, clinical laboratory values and vital signs. No formal inferential analyses will be conducted for safety variables, unless otherwise noted.
  • Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).
  • An AE will be considered treatment-emergent if it occurs after the first dose of investigational product (including the duration of infusion) and within 28 days after a subject’s last dose of investigational product.
  • the overall incidence of subjects having at least one AE will be summarized by dose level.
  • the incidence of TEAEs will be summarized by dose level, system organ class (SOC), and preferred term (PT); each subject will be counted only once per SOC and PT. Similar summaries will be produced for SAEs and AEs leading to discontinuation.
  • SOC system organ class
  • PT preferred term
  • PK parameters will be summarized using descriptive statistics by dose level and visit. Descriptive statistics for serum concentrations will include n, number of subjects with concentrations below the level 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.
  • Example 2 Results from A Phase lb, 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
  • Example 2 Presented herein in Example 2 are certain results of the study conducted according to the methods as described in Example 1.
  • Figure 1 shows CRP concentrations by visit for four patients in the first cohort.
  • Figures 2A and 2B show ferritin concentrations by visit for three patients (two patients in Figure 2A; one patient in Figure 2B) in the first cohort.
  • Figure 3 shows modified Pouchot score by visit for three patients in the first cohort.
  • Figure 4 shows physician global assessment (PhGA) score by visit for three patients in the first cohort.
  • Figure 5 shows patient global assessment (PtGA) score by visit for three patients in the first cohort.
  • a second cohort will be treated according to Example 1: the 14 mg/kg group.
  • Example 3 A Study To Evaluate The Safety And Tolerability, Efficacy, Pharmacokinetics, And Pharmacodynamics of Antibody A In Subjects With Systemiconset Juvenile Idiopathic Arthritis

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Abstract

La présente divulgation concerne des méthodes de traitement de la maladie de Still chez l'adulte (AOSD) et de la forme systémique de l'arthrite idiopathique juvénile (SoJIA), éventuellement associées à des taux élevés d'IL-18, comprenant l'administration à un sujet humain chez lequel a été diagnostiqué une AOSD ou une SoJIA, d'une quantité efficace d'un anticorps anti-IL-18 à certains dosages.
PCT/US2021/064357 2021-12-20 2021-12-20 Méthodes et traitement de la maladie de still chez l'adulte et de la forme systémique de l'arthrite idiopathique juvénile impliquant des anticorps dirigés contre il-18 Ceased WO2023121643A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
PCT/US2021/064357 WO2023121643A1 (fr) 2021-12-20 2021-12-20 Méthodes et traitement de la maladie de still chez l'adulte et de la forme systémique de l'arthrite idiopathique juvénile impliquant des anticorps dirigés contre il-18
AU2021479973A AU2021479973A1 (en) 2021-12-20 2021-12-20 Methods and treatment for adult-onset still's disease and systemic-onset juvenile idiopathic arthritis involving antibodies to il-18
JP2024537408A JP2025500352A (ja) 2021-12-20 2021-12-20 Ｉｌ－１８に対する抗体を要する成人発症スチル病および全身発症型若年性特発性関節炎のための方法および治療
KR1020247024581A KR20240134909A (ko) 2021-12-20 2021-12-20 Il-18에 대한 항체를 포함하는 성인-발병성 스틸병 및 전신-발병성 소아 특발성 관절염에 대한 방법 및 치료
CA3243024A CA3243024A1 (fr) 2021-12-20 2021-12-20 Methodes et traitement de la maladie de still chez l'adulte et de la forme systemique de l'arthrite idiopathique juvenile impliquant des anticorps diriges contre il-18
MX2024007616A MX2024007616A (es) 2021-12-20 2021-12-20 Métodos y tratamiento para la enfermedad de still de inicio en la edad adulta y la artritis idiopática juvenil de inicio sistemico que implica anticuerpos contra il-18.

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PCT/US2021/064357 WO2023121643A1 (fr) 2021-12-20 2021-12-20 Méthodes et traitement de la maladie de still chez l'adulte et de la forme systémique de l'arthrite idiopathique juvénile impliquant des anticorps dirigés contre il-18

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140004128A1 (en) * 2010-12-20 2014-01-02 Medimmune Limited Anti-il-18 antibodies and their uses
US20200377586A1 (en) * 2015-03-05 2020-12-03 Ab2 Bio Sa Il-18 binding protein (il-18bp) and antibodies in inflammatory diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140004128A1 (en) * 2010-12-20 2014-01-02 Medimmune Limited Anti-il-18 antibodies and their uses
US20200377586A1 (en) * 2015-03-05 2020-12-03 Ab2 Bio Sa Il-18 binding protein (il-18bp) and antibodies in inflammatory diseases

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CA3243024A1 (fr) 2025-02-26
MX2024007616A (es) 2024-09-04
KR20240134909A (ko) 2024-09-10
JP2025500352A (ja) 2025-01-09

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