US20190241650A1 - Methods for treating il-6 mediated inflammation without immunosuppression - Google Patents

Methods for treating il-6 mediated inflammation without immunosuppression Download PDF

Info

Publication number
US20190241650A1
US20190241650A1 US16/240,670 US201916240670A US2019241650A1 US 20190241650 A1 US20190241650 A1 US 20190241650A1 US 201916240670 A US201916240670 A US 201916240670A US 2019241650 A1 US2019241650 A1 US 2019241650A1
Authority
US
United States
Prior art keywords
equivalent dose
patient
monthly equivalent
certain embodiments
antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US16/240,670
Other languages
English (en)
Inventor
Madhav N. Devalaraja
Michael H. Davidson
Rahul Kakkar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Corvidia Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Corvidia Therapeutics Inc filed Critical Corvidia Therapeutics Inc
Priority to US16/240,670 priority Critical patent/US20190241650A1/en
Assigned to CORVIDIA THERAPEUTICS, INC. reassignment CORVIDIA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEVALARAJA, MADHAV H., DAVIDSON, MICHAEL H., KAKKAR, Rahul
Priority to US16/396,378 priority patent/US11384143B2/en
Publication of US20190241650A1 publication Critical patent/US20190241650A1/en
Assigned to NOVO NORDISK A/S reassignment NOVO NORDISK A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CORVIDIA THERAPEUTICS, INC.
Priority to US17/708,660 priority patent/US20220227856A1/en
Priority to US17/991,880 priority patent/US20230090473A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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]
    • C07K16/248—IL-6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Chronic inflammation is a characteristic of many diseases, including both the classical rheumatic disorders such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, and inflammatory bowel disease, as well as other systemic diseases that are increasingly understood to be associated with chronic inflammation, such as cardiovascular disease, renal disease, neuroinflammatory diseases, anemias, cancer and aging.
  • the pro-inflammatory cytokine, IL-6 often plays a critical role in chronic inflammation through activation of the JAK-STAT signaling pathway, and IL-6 inhibitors have been developed to treat certain inflammatory disorders in which IL-6 has been shown to contribute significantly to disease etiology.
  • the anti-IL-6 receptor antibody, tocilizumab (ACTEMRA) has been approved for treatment of rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and iatrogenic cytokine release syndrome.
  • the anti-IL-6 receptor antibody, sarilumab (KEVZARA) has been approved to treat adult patients with moderately to severely active rheumatoid arthritis.
  • IL-6 antagonists can be administered at a dose, on a schedule, and for a period sufficient to reduce inflammation without causing immune suppression.
  • methods for treating IL-6-mediated inflammation in a patient comprise: administering an IL-6 antagonist to a patient with IL-6-mediated inflammation at a dose that is sufficient to reduce inflammation without causing immune suppression.
  • the patient has an elevated pre-treatment C-reactive protein (CRP) level.
  • CRP C-reactive protein
  • the pre-treatment CRP level of the patient is at least 2 mg/L. In some embodiments, the pre-treatment CRP level of the patient is at least 4 mg/L. In some embodiments, the pre-treatment CRP level of the patient is at least 6 mg/L. In some embodiments, the pre-treatment CRP level of the patient is at least 10 mg/L.
  • CRP C-reactive protein
  • the patient has an elevated pre-treatment serum IL-6 level.
  • the pre-treatment serum IL-6 level of the patient is at least 4 pg/mL. In some embodiments, the pre-treatment serum IL-6 level of the patient is at least 4 pg/mL. In some embodiments, the pre-treatment serum IL-6 level of the patient is at least 5 pg/mL. In some embodiments, the pre-treatment serum IL-6 level of the patient is at least 10 pg/mL.
  • the inflammation is measured by the level of C-reactive protein (CRP).
  • CRP C-reactive protein
  • the post-treatment CRP level is no more than 2 mg/L. In some embodiments, the post-treatment CRP level is no more than 1 mg/L. In some embodiments, the CRP level is decreased by at least 50% as compared to pre-treatment levels. In some embodiments, the CRP level is decreased by at least 70% as compared to pre-treatment levels. In some embodiments, the CRP level is decreased by at least 80% as compared to pre-treatment levels. In some embodiments, the CRP level is decreased by at least 90% as compared to pre-treatment levels.
  • the immune suppression is measured by absolute neutrophil count (ANC).
  • the post-treatment ANC is at least 500 cells/ ⁇ L. In some embodiments, the post-treatment ANC is at least 1000 cells/ ⁇ L. In some embodiments, the post-treatment ANC is at least 1500 cells/ ⁇ L. In some embodiments, the post-treatment ANC is at least 2000 cells/ ⁇ L. In some embodiments, the ANC is decreased by no more than 2000 cells/ ⁇ L as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 1500 cells/ ⁇ L as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 1000 cells/ ⁇ L as compared to pre-treatment levels.
  • the ANC is decreased by no more than 500 cells/ ⁇ L as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 50% as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 40% as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 30% as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 20% as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 10% as compared to pre-treatment levels. In some embodiments, the ANC is not decreased as compared to pre-treatment levels.
  • the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 30% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 20% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 10% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is about 25% of a monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.
  • the IL-6 antagonist is administered at a monthly equivalent dose that is about 20% of a monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is about 15% of a monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is about 10% of a monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is about 5% of a monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.
  • the IL-6 antagonist is an anti-IL-6 antibody.
  • the anti-IL-6 antibody is COR-001.
  • COR-001 is administered intravenously at a monthly equivalent dose of 2-40 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 2 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 4 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 6 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 10 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 20 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 40 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of 3-70 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 3 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 7 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 10 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 17 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 35 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 70 mg.
  • the anti-IL-6 antibody is siltuximab.
  • siltuximab is administered intravenously at a monthly equivalent dose of 50-500 mg.
  • siltuximab is administered intravenously at a monthly equivalent dose of about 50 mg.
  • siltuximab is administered intravenously at a monthly equivalent dose of about 100 mg.
  • siltuximab is administered intravenously at a monthly equivalent dose of about 150 mg.
  • siltuximab is administered intravenously at a monthly equivalent dose of about 200 mg.
  • siltuximab is administered intravenously at a monthly equivalent dose of about 300 mg.
  • siltuximab is administered intravenously at a monthly equivalent dose of about 500 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of 80-800 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 80 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 160 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 240 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 320 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 480 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 800 mg.
  • the anti-IL-6 antibody is gerilimzumab.
  • gerilimzumab is administered intravenously at a monthly equivalent dose of 0.075-1.8 mg. In some embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.075 mg. In some embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.12 mg. In some embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.3 mg. In some embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.6 mg.
  • gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.9 mg. In some embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 1.8 mg. In some embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of 0.125-3 mg. In some embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 0.125 mg. In some embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 0.2 mg. In some embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 0.5 mg.
  • gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 1 mg. In some embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 1.5 mg. In some embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 3 mg.
  • the anti-IL-6 antibody is sirukumab.
  • sirukumab is administered intravenously at a monthly equivalent dose of 1.5-60 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 1.5 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 3 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 6 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 12 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 36 mg.
  • sirukumab is administered intravenously at a monthly equivalent dose of about 60 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of 2.5-100 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 2.5 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 5 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 10 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 20 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 60 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 100 mg.
  • the anti-IL-6 antibody is clazakizumab.
  • clazakizumab is administered intravenously at a monthly equivalent dose of 3-60 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of about 3 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of about 6 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of about 12 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of about 24 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of about 36 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of about 60 mg. In some embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of 5-100 mg. In some embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 5 mg. In some embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 10 mg. In some embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 20 mg. In some embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 40 mg. In some embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 60 mg. In some embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 100 mg.
  • the anti-IL-6 antibody is olokizumab.
  • olokizumab is administered intravenously at a monthly equivalent dose of 1.8-60 mg.
  • olokizumab is administered intravenously at a monthly equivalent dose of about 1.8 mg.
  • olokizumab is administered intravenously at a monthly equivalent dose of about 3.6 mg.
  • olokizumab is administered intravenously at a monthly equivalent dose of about 9 mg.
  • olokizumab is administered intravenously at a monthly equivalent dose of about 18 mg.
  • olokizumab is administered intravenously at a monthly equivalent dose of about 45 mg. In some embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 60 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of 3-100 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 3 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 6 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 15 mg.
  • olokizumab is administered subcutaneously at a monthly equivalent dose of about 30 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 72 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 100 mg.
  • the anti-IL-6 antibody is VX30 (VOP-R003; Vaccinex). In some embodiments, VX30 (VOP-R003; Vaccinex) is administered intravenously. In some embodiments, VX30 (VOP-R003; Vaccinex) is administered subcutaneously.
  • the anti-IL-6 antibody is EB-007 (EBI-029; Eleven Bio). In some embodiments, EB-007 (EBI-029; Eleven Bio) is administered intravenously. In some embodiments, EB-007 (EBI-029; Eleven Bio) is administered subcutaneously.
  • the anti-IL-6 antibody is FM101 (Femta Pharmaceuticals, Lonza). In some embodiments, FM101 (Femta Pharmaceuticals, Lonza) is administered intravenously. In some embodiments, FM101 (Femta Pharmaceuticals, Lonza) is administered subcutaneously.
  • the IL-6 antagonist is an anti-IL-6R antibody.
  • the anti-IL-6R antibody is tocilizumab.
  • tocilizumab is administered intravenously at a monthly equivalent dose of 50-500 mg.
  • tocilizumab is administered intravenously at a monthly equivalent dose of about 50 mg.
  • tocilizumab is administered intravenously at a monthly equivalent dose of about 100 mg.
  • tocilizumab is administered intravenously at a monthly equivalent dose of about 150 mg.
  • tocilizumab is administered intravenously at a monthly equivalent dose of about 250 mg.
  • tocilizumab is administered intravenously at a monthly equivalent dose of about 350 mg.
  • tocilizumab is administered intravenously at a monthly equivalent dose of about 500 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of 80-800 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 80 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 160 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 240 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 400 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 560 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 800 mg.
  • the anti-IL-6R antibody is sarilumab.
  • sarilumab is administered intravenously at a monthly equivalent dose of 12-120 mg.
  • sarilumab is administered intravenously at a monthly equivalent dose of about 12 mg.
  • sarilumab is administered intravenously at a monthly equivalent dose of about 24 mg.
  • sarilumab is administered intravenously at a monthly equivalent dose of about 48 mg.
  • sarilumab is administered intravenously at a monthly equivalent dose of about 60 mg.
  • sarilumab is administered intravenously at a monthly equivalent dose of about 72 mg.
  • sarilumab is administered intravenously at a monthly equivalent dose of about 120 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of 20-200 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 20 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 40 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 80 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 100 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 120 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 200 mg.
  • the anti-IL-6R antibody is vobarilizumab.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of 4-120 mg.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of about 4 mg.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of about 6 mg.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of about 30 mg.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of about 60 mg.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of about 84 mg. In some embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 120 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of 7-200 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 7 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 10 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 50 mg.
  • vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 100 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 140 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 200 mg.
  • the IL-6 antagonist is a JAK inhibitor. In some embodiments, the IL-6 antagonist is a STAT3 inhibitor.
  • the patient has a hepcidin-mediated disorder.
  • the patient has kidney disease. In some embodiments, the patient has chronic kidney disease. In some embodiments, the patient has K D OQI stage 1-5 chronic kidney disease. In some embodiments, the patient has K D OQI stage 3-5 chronic kidney disease. In some embodiments, the patient is not on dialysis. In some embodiments, the patient has K D OQI stage 5 chronic kidney disease. In some embodiments, the patient is on dialysis. In some embodiments, the patient has cardiorenal syndrome (CRS). In some embodiments, the patient has CRS Type 4.
  • CRS cardiorenal syndrome
  • the patient has cardiovascular disease. In some embodiments, the patient has diuretic resistant heart failure. In some embodiments, the patient has congestive heart failure (CHF). In some embodiments, the patient has congestive heart failure (CHF) with reduced ejection fraction. In some embodiments, the patient has congestive heart failure (CHF) with mid-range ejection fraction. In some embodiments, the patient has congestive heart failure (CHF) with preserved ejection fraction. In some embodiments, the patient has acute coronary syndrome. In some embodiments, the patient has atherosclerosis.
  • the patient has anemia. In some embodiments, the patient has anemia of chronic disease. In some embodiments, the patient has iron-refractory iron-deficiency anemia (IRIDA).
  • IRIDA iron-refractory iron-deficiency anemia
  • the patient has diabetes. In some embodiments, the patient has type II diabetes. In some embodiments, the patient has insulin-resistant diabetes.
  • the patient has liver disease. In some embodiments, the patient has non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the patient has osteoporosis.
  • the patient has depression.
  • the patient has asthma.
  • the patient has neuroinflammatory disorder. In some embodiments, the patient has Alzheimer's disease. In some embodiments, the patient has Parkinson's disease. In some embodiments, the patient has multiple sclerosis. In some embodiments, the patient has amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the patient has age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the patient has cancer.
  • the cancer is selected from the group consisting of: solid tumors, small cell lung cancer, non-small cell lung cancer, hematological cancer, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), lymphomas, Hodgkin's lymphoma and hepatic adenoma.
  • patient has skin disease.
  • the method prevents aging in the patient.
  • methods for treating inflammation in a patient with cardiovascular disease comprise: administering an IL-6 antagonist to a patient with cardiovascular disease and CRP level greater than 2 mg/L at a dose that is sufficient to reduce CRP levels to 2 mg/L or less without causing neutropenia.
  • the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 30% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 20% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 10% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.
  • methods for treating inflammation in a patient with chronic kidney disease comprise: administering an IL-6 antagonist to a patient with CK D and a CRP level greater than 2 mg/L at a dose that is sufficient to reduce CRP levels to 2 mg/L or less without causing neutropenia.
  • the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 30% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 20% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 10% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.
  • FIG. 1 presents the dose escalation schematic for the phase 1/phase 2 randomized, double-blind, placebo-controlled trial of COR-001 in hemodialysis patients described in Example 1.
  • FIG. 2 shows the timeline and the efficacy analysis of the treatment phase and the safety follow-up phase.
  • FIGS. 3A and 3B show the results of C-reactive protein (CRP) responder analysis after treatment with COR-001 (anti-IL-6) or canakinumab (anti-IL1(3).
  • FIG. 3A shows the C-reactive protein responder rate after intravenous treatment with COR-001 in patients with stage 5 chronic kidney disease who were on dialysis in the clinical trial described in Example 1.
  • the baseline hsCRP was 12.4 mg/L.
  • Responder was defined as Week 12 average hsCRP ⁇ 2 mg/L.
  • FIG. 3B shows the C-reactive protein responder rate after treatment with canakinumab in the CANTOS trial, as described in the research literature.
  • the baseline hsCRP was 5.5 mg/L.
  • Responder was defined as 3-month hsCRP ⁇ 2 mg/L.
  • FIG. 4 shows the results of hemoglobin responder analysis after treatment with COR-001 at doses of 2 mg, 6 mg, and 20 mg.
  • Hemoglobin responder was defined as increase by 1 g/dL or more after Day 29. Investigators were not permitted to change ESA dosing until after Day 29.
  • FIG. 5 shows the effect of COR-001 on the diastolic cardiac parameter, NT-proBNP.
  • FIGS. 6A and 6B show the adverse responder rate for neutrophils and platelets.
  • FIG. 6A shows the neutrophils adverse responder rate.
  • An Adverse Responder was defined as Week 12 average neutrophils ⁇ 2 ⁇ 10 6 /mL.
  • FIG. 6B shows the platelets adverse responder rate.
  • Adverse responder was defined as Week 12 average platelets ⁇ 100 ⁇ 10 6 /mL.
  • IL-6 interleukin 6
  • IL-6 polypeptide refers to a polypeptide or fragment thereof having at least about 85% or greater amino acid identity to the amino acid sequence provided at NCBI Accession No. NP_000591 and having IL-6 biological activity.
  • IL-6 is a pleotropic cytokine with multiple biologic functions.
  • Exemplary IL-6 biological activities include immunostimulatory and pro-inflammatory activities.
  • An exemplary IL-6 amino acid sequence is provided below:
  • SEQ ID NO: 1 MCVGARRLGR GPCAALLLLG LGLSTVTGLH CVGDTYPSND RCCHECRPGN GMVSRCSRSQ 61 NTVCRPCGPG FYNDVVSSKP CKPCTWCNLR SGSERKQLCT ATQDTVCRCR AGTQPLDSYK 121 PGVDCAPCPP GHFSPGDNQA CKPWTNCTLA GKHTLQPASN SSDAICEDRD PPATQPQETQ 181 GPPARPITVQ PTEAWPRTSQ GPSTRPVEVP GGRAVAAILG LGLVLGLLGP LAILLALYLL 241 RRDQRLPPDA HKPPGGGSFR TPIQEEQADA HSTLAKI
  • interleukin 6 (IL-6) nucleic acid refers to a polynucleotide encoding an interleukin 6 (IL-6) polypeptide.
  • An exemplary interleukin 6 (IL-6) nucleic acid sequence is provided at NCBI Accession No. NM 000600. The exemplary sequence at NCBI Accession No. NM 000600 is provided below:
  • interleukin 6 receptor (IL-6R) complex refers to a protein complex comprising an IL-6 receptor subunit alpha (IL-6R ⁇ ) and interleukin 6 signal transducer glycoprotein 130 (gp130), also termed interleukin 6 receptor subunit ⁇ (IL-6R ⁇ ).
  • interleukin 6 receptor subunit a (IL-6R ⁇ ) polypeptide refers to a polypeptide or fragment thereof having at least about 85% or greater amino acid identity to the amino acid sequence provided at NCBI Accession No. NP 000556 or NP 852004 and having IL-6 receptor biological activity.
  • Exemplary IL-6R ⁇ biological activities include binding to IL-6, binding to glycoprotein 130 (gp130), and regulation of cell growth and differentiation.
  • An exemplary IL-6R sequence is provided below:
  • glycoprotein 130 gp130
  • IL-6R ⁇ interleukin 6 receptor subunit ⁇ polypeptide
  • gp130 amino acid sequence provided at NCBI Accession No. NP_002175, NP_786943, or NP_001177910 and having IL-6 receptor biological activity.
  • Exemplary IL-6R13 biological activities include binding to IL-6R ⁇ , IL-6 receptor signaling activity, and regulation of cell growth, differentiation, hepcidin expression etc.
  • An exemplary IL-6R ⁇ sequence is provided below:
  • IL-6 antagonist refers an agent that is capable of decreasing the biological activity of IL-6.
  • IL-6 antagonists include agents that decrease the level of IL-6 polypeptide in serum, including agents that decrease the expression of an IL-6 polypeptide or nucleic acid; agents that decrease the ability of IL-6 to bind to the IL-6R; agents that decrease the expression of the IL-6R; and agents that decrease signal transduction by the IL-6R receptor when bound by IL-6.
  • the IL-6 antagonist decreases IL-6 biological activity by at least about 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.
  • IL-6 antagonists include IL-6 binding polypeptides, such as anti-IL-6 antibodies and antigen binding fragments or derivatives thereof; IL-6R binding polypeptides, such as anti-IL-6R antibodies and antigen binding fragments or derivatives thereof; and synthetic chemical molecules, such as JAK1 and JAK3 inhibitors.
  • IL-6 antibody or “anti-IL-6 antibody” refers to an antibody that specifically binds IL-6.
  • Anti-IL-6 antibodies include monoclonal and polyclonal antibodies that are specific for IL-6, and antigen-binding fragments or derivatives thereof. IL-6 antibodies are described in greater detail below.
  • IL-6 mediated inflammation or “IL-6 mediated inflammatory disorder” refers to inflammation or inflammation related disorder in which IL-6 is known or suspected to contribute to the etiology or symptoms of the inflammation.
  • CRP C-reactive protein
  • CRP refers to a polypeptide or fragment thereof having at least about 85% or greater amino acid identity to the amino acid sequence provided at NCBI Accession No. NP_000558 and having complement activating activity. CRP levels increase in response to inflammation, and can be measured with an hsCRP (high-sensitivity C-reactive protein) test.
  • An exemplary CRP sequence is provided below:
  • hepcidin refers to a polypeptide having at least about 85% or greater amino acid identity to the amino acid sequence provided at NCBI Accession No. NP 066998 (“hepcidin preprotein”), or biologically active fragment thereof.
  • exemplary hepcidin biological activities include binding and reducing the levels of the iron export channel ferroportin, inhibiting iron transport, inhibiting intestinal iron absorption, and inhibiting iron release from macrophages and the liver.
  • An exemplary hepcidin preprotein amino acid sequence is provided below:
  • hepcidin exists in various forms, including as a preprohormone (amino acids 25-84), prohormone (amino acids 25-84), and mature forms termed hepcidin-25 (amino acids 60-84), hepcidin-22 (amino acids 63-84), and hepcidin-20 (amino acids 65-84).
  • a “hepcidin-mediated disorder” is any disorder in which hepcidin expression contributes to the etiology of the disorder or any of its symptoms.
  • immune suppression or “immunosuppression” refers to a reduction of the activation or efficacy of the immune system. Immune suppression can be measured by the number of white blood cells, such as neutrophils.
  • neutrophil of “neutrocyte” refers to a type of white blood cell that is an essential part of the innate immune system.
  • the absolute neutrophil count (ANC) can be used in diagnosis and prognosis.
  • Low neutrophil counts are termed neutropenia.
  • agent refers to any compound or composition suitable to be administered in therapy, and explicitly includes chemical compounds; proteins, including antibodies or antigen-binding fragments thereof; peptides; and nucleic acid molecules.
  • subject refers to a human or non-human mammal, including, but not limited to, bovine, equine, canine, ovine, feline, and rodent, including murine and rattus, subjects.
  • a “patient” is a human subject in need of treatment.
  • the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating a disorder, and/or signs or symptoms associated therewith, or slowing or halting the progression thereof. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • pre-treatment means prior to the first administration of an IL-6 antagonist according the methods described herein. Pre-treatment does not exclude, and often includes, the prior administration of treatments other than an IL-6 antagonist.
  • post-treatment means after the administration of an IL-6 antagonist according the methods described herein. Post-treatment includes after any administration of an IL-6 antagonist at any dosage described herein. Post-treatment also includes after the treatment phase of an IL-6 antagonist.
  • biological sample refers to any tissue, cell, fluid, or other material derived from an organism (e.g., human subject).
  • the biological sample is serum or blood.
  • antibody constant region residue numbering is according to the EU index as in Kabat.
  • methods of treating IL-6-mediated inflammation in a patient comprise administering an IL-6 antagonist to a patient with IL-6-mediated inflammation at a dose that is sufficient to reduce inflammation without causing immune suppression.
  • the patient has an IL-6-mediated inflammation.
  • the patient has elevated pre-treatment levels of C-reactive protein (CRP).
  • CRP C-reactive protein
  • the patient has a pre-treatment CRP level at least 2 mg/L. In some embodiments, the patient has a pre-treatment CRP level at least 2 mg/L, 2.5 mg/L, 3 mg/L, 3.5 mg/L, 4 mg/L, 4.5 mg/L, or 5 mg/L. In some embodiments, the patient has pre-treatment CRP levels at least 7.5 mg/L, 10 mg/L, 12.5 mg/L, or 15 mg/L. In various embodiments, the patient has a pre-treatment CRP level at least 2 mg/L. In various embodiments, the patient has a pre-treatment CRP level at least 2.5 mg/L. In various embodiments, the patient has a pre-treatment CRP level at least 5 mg/L.
  • the patient has a pre-treatment CRP level at least 7.5 mg/L. In various embodiments, the patient has a pre-treatment CRP level at least 10 mg/L. In various embodiments, the patient has a pre-treatment CRP level at least 12.5 mg/L. In various embodiments, the patient has a pre-treatment CRP level at least 15 mg/L.
  • the patient has elevated pre-treatment serum levels of IL-6.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml. In various embodiments, the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml, at least 3 pg/ml, at least 4 pg/ml, at least 5 pg/ml, at least 6 pg/ml, at least 7 pg/ml, at least 8 pg/ml, at least 9 pg/ml, at least 10 pg/ml, at least 11 pg/ml, at least 12 pg/ml, at least 13 pg/ml, at least 14 pg/ml, or at least 15 pg/ml.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 2.5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 7.5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 12.5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 15 pg/ml.
  • the patient has elevated pre-treatment serum levels of CRP and elevated pre-treatment IL-6 levels.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre-treatment CRP level at least 2 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre-treatment CRP level at least 2.5 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre-treatment CRP level at least 5 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre-treatment CRP level at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml and a pre-treatment CRP level at least 2 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml and a pre-treatment CRP level at least 2.5 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml and a pre-treatment CRP level at least 5 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml and a pre-treatment CRP level at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml and a pre-treatment CRP level at least 2 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml and a pre-treatment CRP level at least 2.5 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml and a pre-treatment CRP level at least 5 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml and a pre-treatment CRP level at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level at least 2 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level at least 2.5 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level at least 5 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level at least 10 mg/L.
  • the IL-6 antagonist is administered at a dose sufficient to reduce the patient's free serum IL-6 levels below pre-treatment levels.
  • the free serum IL-6 level is decreased by at least 10% as compared to pre-treatment levels. In various embodiments, the free serum IL-6 level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 20% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 30% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 40% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 50% as compared to pre-treatment levels.
  • the free serum IL-6 level is decreased by at least 60% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 70% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 80% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 90% as compared to pre-treatment levels.
  • the IL-6 antagonist is administered at a dose sufficient to reduce the patient's CRP levels below pre-treatment levels. In some embodiments, the IL-6 mediated inflammation is measured by the CRP levels.
  • the post-treatment CRP level is no more than 5 mg/L. In certain embodiments, the post-treatment CRP level is no more than 2.5 mg/L. In certain embodiments, the post-treatment CRP level is no more than 2 mg/L. In certain embodiments, the post-treatment CRP level is no more than 1 mg/L.
  • the CRP level is decreased by at least 10% as compared to pre-treatment levels. In various embodiments, the CRP level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 20% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 30% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 40% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 50% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 60% as compared to pre-treatment levels.
  • the CRP level is decreased by at least 70% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 80% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 90% as compared to pre-treatment levels.
  • the IL-6 antagonist is administered at a dose sufficient to reduce inflammation without causing immune suppression.
  • the immune suppression of the patient is measured by Absolute Neutrophil Count (ANC).
  • ANC Absolute Neutrophil Count
  • the post-treatment ANC is at least 300 cells/ ⁇ L. In various embodiments, the post-treatment ANC is at least 500 cells/ ⁇ L, 600 cells/ ⁇ L, 700 cells/ ⁇ L, 800 cells/ ⁇ L, 900 cells/ ⁇ L, 1000 cells/ ⁇ L, 1100 cells/ ⁇ L, 1200 cells/ ⁇ L, 1300 cells/ ⁇ L, 1400 cells/ ⁇ L, 1500 cells/ ⁇ L, 1600 cells/ ⁇ L, 1700 cells/ ⁇ L, 1800 cells/ ⁇ L, 1900 cells/ ⁇ L, or 2000 cells/ ⁇ L. In certain embodiments, the post-treatment ANC is at least 500 cells/ ⁇ L. In certain embodiments, the post-treatment ANC is at least 750 cells/ ⁇ L.
  • the post-treatment ANC is at least 1000 cells/ ⁇ L. In certain embodiments, the post-treatment ANC is at least 1250 cells/ ⁇ L. In certain embodiments, the post-treatment ANC is at least 1500 cells/ ⁇ L. In certain embodiments, the post-treatment ANC is at least 1750 cells/ ⁇ L. In certain embodiments, the post-treatment ANC is at least 2000 cells/ ⁇ L.
  • the ANC is decreased by no more than 2500 cells/ ⁇ L as compared to pre-treatment levels.
  • the ANC is decreased by no more than 2000 cells/ ⁇ L, 1900 cells/ ⁇ L, 1800 cells/ ⁇ L, 1700 cells/ ⁇ L, 1600 cells/ ⁇ L, 1500 cells/ ⁇ L, 1400 cells/ ⁇ L, 1300 cells/ ⁇ L, 1200 cells/ ⁇ L, 1100 cells/ ⁇ L, 1000 cells/ ⁇ L, 900 cells/ ⁇ L, 800 cells/ ⁇ L, 700 cells/ ⁇ L, 600 cells/ ⁇ L, or 500 cells/ ⁇ L, as compared to pre-treatment levels.
  • the ANC is decreased by no more than 2000 cells/ ⁇ L as compared to pre-treatment levels.
  • the ANC is decreased by no more than 1750 cells/ ⁇ L as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 1500 cells/ ⁇ L as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 1250 cells/ ⁇ L as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 1000 cells/ ⁇ L as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 750 cells/ ⁇ L as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 500 cells/ ⁇ L as compared to pre-treatment levels.
  • the ANC is decreased by no more than 70% as compared to pre-treatment levels. In various embodiments, the ANC is decreased by no more than 60%, 50%, 40%, 30%, 20%, 10%, or 5% as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 60% as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 50% as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 40% as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 30% as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 20% as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 10% as compared to pre-treatment levels. In certain embodiments, the ANC is decreased by no more than 5% as compared to pre-treatment levels.
  • the ANC is not decreased as compared to pre-treatment levels.
  • the IL-6 antagonist is administered at a dose sufficient to reduce the patient's lipoprotein(a) levels below pre-treatment levels.
  • the lipoprotein(a) level is decreased by at least 10% as compared to pre-treatment levels. In various embodiments, the lipoprotein(a) level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels. In certain embodiments, the lipoprotein(a) level is decreased by at least 20% as compared to pre-treatment levels. In certain embodiments, the lipoprotein(a) level is decreased by at least 30% as compared to pre-treatment levels. In certain embodiments, the lipoprotein(a) level is decreased by at least 40% as compared to pre-treatment levels. In certain embodiments, the lipoprotein(a) level is decreased by at least 50% as compared to pre-treatment levels.
  • the lipoprotein(a) level is decreased by at least 60% as compared to pre-treatment levels. In certain embodiments, the lipoprotein(a) level is decreased by at least 70% as compared to pre-treatment levels. In certain embodiments, the lipoprotein(a) level is decreased by at least 80% as compared to pre-treatment levels. In certain embodiments, the lipoprotein(a) level is decreased by at least 90% as compared to pre-treatment levels.
  • the IL-6 antagonist is administered at a dose sufficient to reduce the patient's lipoprotein(a) levels without significantly increasing the patent's low-density lipoprotein (LDL) levels.
  • LDL low-density lipoprotein
  • the LDL level is increased by no more than 5% as compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 4% as compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 3% as compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 2% as compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 1% as compared to pre-treatment levels.
  • the LDL level is not increased as compared to pre-treatment levels.
  • the patient has an IL-6 mediated inflammatory disorder.
  • the IL-6 mediated inflammatory disorder is not a hepcidin-mediated disorder.
  • Hepcidin-mediated disorders are described in US 2017/0029499, the disclosure of which is incorporated herein by reference in its entirety.
  • the IL-6 mediated inflammatory disorder is a hepcidin-mediated disorder.
  • Hepcidin-mediated disorders are described in US 2017/0029499, the disclosure of which is incorporated herein by reference in its entirety.
  • the patient has a hepcidin-mediated disorder and at least one copy of the major allele at the TMPRSS6 rs855791 SNP (amino acid 736A).
  • the patient has a hepcidin-mediated disorder and is homozygous for the minor allele at the TMPRSS6 rs855791 SNP (amino acid 736V).
  • the patient has a hepcidin-mediated disorder and unknown genotype at the TMPRSS6 rs855791 SNP.
  • the IL-6 mediated inflammatory disorder is a non-autoimmune IL-6 mediated inflammatory disorder.
  • the patient has an IL-6 mediated disorder other than rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, or systemic juvenile idiopathic arthritis.
  • the patient has kidney disease.
  • the kidney disease is chronic kidney disease (CK D ).
  • the patient has K D OQI stage 1-5 chronic kidney disease. In some embodiments, the patient has K D OQI stage 3-5 chronic kidney disease. In some embodiments, the patient has K D OQI stage 1 chronic kidney disease, K D OQI stage 2 chronic kidney disease, K D OQI stage 3 chronic kidney disease, K D OQI stage 4 chronic kidney disease, or K D OQI stage 5 chronic kidney disease. In certain embodiments, the patient has K D OQI stage 5 chronic kidney disease.
  • the patient is on dialysis. In some embodiments, the patient is not on dialysis. In certain embodiment, the patient has K D OQI stage 3-5 chronic kidney disease, wherein the patient is not on dialysis. In certain embodiment, the patient has K D OQI stage 5 chronic kidney disease, wherein the patient is on dialysis.
  • the patient has cardiorenal syndrome (CRS). In certain embodiments, the patient has CRS Type 4.
  • CRS cardiorenal syndrome
  • the patient has been treated with dialysis.
  • the patient has cardiovascular disease.
  • the patient has had a previous myocardial infarction.
  • the patient has had a previous myocardial infarction and has a CRP level of 2 mg/L or more.
  • the patient has suffered a myocardial infarction within the 60 days prior to first administration of an IL-6 antagonist. In particular embodiments, the patient has suffered a myocardial infarction within the 30 days, 14 days, 7 days, 48 hours, or 24 hours prior to first administration of an IL-6 antagonist.
  • the patient has atherosclerosis but has not had a myocardial infarction.
  • the patient has atherosclerosis, has not had a myocardial infarction, and has a CRP level of 2 mg/L or more.
  • the cardiovascular disease is congestive heart failure (CHF).
  • CHF congestive heart failure
  • the patient has congestive heart failure (CHF) with reduced ejection fraction.
  • the patient has congestive heart failure (CHF) with mid-range ejection fraction.
  • the patient has congestive heart failure (CHF) with preserved ejection fraction.
  • the IL-6 mediated inflammatory disorder is heart failure that is not diuretic resistant.
  • Diuretic resistant heart failure is described in WO 2018/144773, the disclosure of which is incorporated herein by reference in its entirety.
  • the cardiovascular disease is diuretic resistant heart failure.
  • Diuretic resistant heart failure is described in WO 2018/144773, the disclosure of which is incorporated herein by reference in its entirety.
  • the cardiovascular disease is acute coronary syndrome.
  • the IL-6 antagonist is administered at a dose sufficient to reduce nonfatal myocardial infarction, nonfatal stroke, and/or cardiovascular death. In some embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce the risk of heart failure. In some embodiments, the IL-6 antagonist is administered at a dose sufficient to increase cardiac function. In some embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce fibrosis after acute myocardial infarction.
  • the patient has anemia.
  • the patient has anemia of chronic disease. In some embodiments, the patient has iron-refractory iron-deficiency anemia (IRIDA).
  • IRIDA iron-refractory iron-deficiency anemia
  • the patient has been treated with an erythropoiesis-stimulating agent (ESA).
  • ESA erythropoiesis-stimulating agent
  • the patient has been treated with iron supplementation.
  • the patient has been treated with transfusion of blood or packed red blood cells.
  • the IL-6 antagonist is administered at a dose sufficient to reverse functional iron deficiency.
  • the patient has diabetes. In certain embodiments, the patient has type II diabetes. In certain embodiments, the patient has insulin-resistant diabetes.
  • the patient has liver disease. In certain embodiments, the patient has non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the patient has osteoporosis.
  • the patient has depression.
  • the patient has asthma.
  • the patient has neuroinflammatory disorder. In certain embodiments, the patient has Alzheimer's disease. In certain embodiments, the patient has Parkinson's disease. In certain embodiments, the patient has multiple sclerosis. In certain embodiments, the patient has amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the patient has age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the patient has cancer.
  • the cancer is selected from the group consisting of: solid tumors, small cell lung cancer, non-small cell lung cancer, hematological cancer, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), lymphomas, and Hodgkin's lymphoma.
  • the patient has skin disease, such as atopic dermatitis or psoriasis.
  • the method prevents aging in the patient.
  • the IL-6 antagonist used in the methods described herein is capable of decreasing the biological activity of IL-6.
  • the IL-6 antagonist is an anti-IL-6 antibody or antigen-binding fragment or derivative thereof.
  • the anti-IL-6 antibody neutralizes the biological activity of IL-6. In some embodiments, the neutralizing antibody prevents binding of IL-6 to the IL-6 receptor.
  • the IL-6 antagonist is an anti-IL-6 monoclonal antibody. In some embodiments, the IL-6 antagonist is a polyclonal composition comprising a plurality of species of anti-IL-6 antibodies, each of the plurality having unique CDRs.
  • the anti-IL-6 antibody is a Fab, Fab′, F(ab′) 2 , Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody, single variable domain antibody, linear antibody, or V domain antibody.
  • the anti-IL-6 antibody comprises a scaffold.
  • the scaffold is Fc, optionally human Fc.
  • the anti-IL-6 antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.
  • the anti-IL-6 antibody comprises a heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.
  • the IL-6 antagonist is immunoconjugate or fusion protein comprising an IL-6 antigen-binding fragment.
  • the antibody is bispecific or multispecific, with at least one of the antigen-binding portions having specificity for IL-6.
  • the antibody is fully human. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric and has non-human V regions and human C region domains. In some embodiments, the antibody is murine.
  • the anti-IL-6 antibody has a K D for binding human IL-6 of less than 100 nM. In some embodiments, the anti-IL-6 antibody has a K D for binding human IL-6 of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nM. In particular embodiments, the anti-IL-6 antibody has a K D for binding human IL-6 of less than 5 nM, 4 nM, 3 nM, or 2 nM. In selected embodiments, the anti-IL-6 antibody has a K D for binding human IL-6 of less than 1 nM, 750 pM, or 500 pM. In specific embodiments, the anti-IL-6 antibody has a K D for binding human IL-6 of no more than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM.
  • the anti-IL-6 antibody has an elimination half-life following intravenous administration of at least 7 days. In certain embodiments, the anti-IL-6 antibody has an elimination half-life of at least 14 days, at least 21 days, or at least 30 days.
  • the anti-IL-6 antibody has a human IgG constant region with at least one amino acid substitution that extends serum half-life as compared to the unsubstituted human IgG constant domain.
  • the IgG constant domain comprises substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is a substitution with tyrosine, the amino acid substitution at amino acid residue 254 is a substitution with threonine, and the amino acid substitution at amino acid residue 256 is a substitution with glutamic acid (“YTE”).
  • YTE glutamic acid
  • the IgG constant domain comprises substitutions selected from T250Q/M428L (Hinton et al., J. Immunology 176:346-356 (2006)); N434A (Yeung et al., J. Immunology 182:7663-7671 (2009)); or T307A/E380A/N434A (Petkova et al., International Immunology, 18: 1759-1769 (2006)).
  • the elimination half-life of the anti-IL-6 antibody is increased by utilizing the FcRN-binding properties of human serum albumin.
  • the antibody is conjugated to albumin (Smith et al., Bioconjug. Chem., 12: 750-756 (2001)).
  • the anti-IL-6 antibody is fused to bacterial albumin-binding domains (Stork et al., Prot. Eng. Design Science 20: 569-76 (2007)).
  • the anti-IL-6 antibody is fused to an albumin-binding peptide (Nguygen et al., Prot Eng Design Sel 19: 291-297 (2006)).
  • the anti-IL-6 antibody is bispecific, with one specificity being to IL-6, and one specificity being to human serum albumin (Ablynx, WO 2006/122825 (bispecific Nanobody)).
  • the elimination half-life of the anti-IL-6 antibody is increased by PEGylation (Melmed et al., Nature Reviews Drug Discovery 7: 641-642 (2008)); by HPMA copolymer conjugation (Lu et al., Nature Biotechnology 17: 1101-1104 (1999)); by dextran conjugation ( Nuclear Medicine Communications, 16: 362-369 (1995)); by conjugation with homo-amino-acid polymers (HAPs; HAPylation) (Schlapschy et al., Prot Eng Design Sel 20: 273-284 (2007)); or by polysialylation (Constantinou et al., Bioconjug. Chem. 20: 924-931 (2009)).
  • the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of COR-001.
  • the COR-001 antibody also known as MEDI5117
  • the antibody or antigen-binding portion thereof comprises the COR-001 heavy chain V region and light chain V region.
  • the antibody is the full-length COR-001 antibody.
  • the COR-001 antibody has the following CDR and heavy and light chain sequences:
  • the anti-IL-6 antibody is a derivative of COR-001.
  • the COR-001 derivative includes one or more amino acid substitutions in the COR-001 heavy and/or light chain V regions.
  • the COR-001 derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the COR-001 anti-IL-6 antibody, while retaining specificity for human IL-6.
  • the COR-001 derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of COR-001.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the COR-001 derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of COR-001.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6).
  • the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of siltuximab.
  • the antibody or antigen-binding portion thereof comprises the siltuximab heavy chain V region and light chain V region.
  • the antibody is the full-length siltuximab antibody.
  • the anti-IL-6 antibody is a derivative of siltuximab.
  • the siltuximab derivative includes one or more amino acid substitutions in the siltuximab heavy and/or light chain V regions.
  • the siltuximab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the siltuximab anti-IL-6 antibody, while retaining specificity for human IL-6.
  • the siltuximab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of siltuximab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the siltuximab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of siltuximab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6).
  • the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of gerilimzumab.
  • the antibody or antigen-binding portion thereof comprises the gerilimzumab heavy chain V region and light chain V region.
  • the antibody is the full-length gerilimzumab antibody.
  • the anti-IL-6 antibody is a derivative of gerilimzumab.
  • the gerilimzumab derivative includes one or more amino acid substitutions in the gerilimzumab heavy and/or light chain V regions.
  • the gerilimzumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the gerilimzumab anti-IL-6 antibody, while retaining specificity for human IL-6.
  • the gerilimzumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of gerilimzumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the gerilimzumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of gerilimzumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6).
  • the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of sirukumab.
  • the antibody or antigen-binding portion thereof comprises the sirukumab heavy chain V region and light chain V region.
  • the antibody is the full-length sirukumab antibody.
  • the anti-IL-6 antibody is a derivative of sirukumab.
  • the sirukumab derivative includes one or more amino acid substitutions in the sirukumab heavy and/or light chain V regions.
  • the sirukumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the sirukumab anti-IL-6 antibody, while retaining specificity for human IL-6.
  • the sirukumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of sirukumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the sirukumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of sirukumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6).
  • the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of clazakizumab.
  • the antibody or antigen-binding portion thereof comprises the clazakizumab heavy chain V region and light chain V region.
  • the antibody is the full-length clazakizumab antibody.
  • the anti-IL-6 antibody is a derivative of clazakizumab.
  • the clazakizumab derivative includes one or more amino acid substitutions in the clazakizumab heavy and/or light chain V regions.
  • the clazakizumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the clazakizumab anti-IL-6 antibody, while retaining specificity for human IL-6.
  • the clazakizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of clazakizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the clazakizumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of clazakizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6).
  • the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of olokizumab.
  • the antibody or antigen-binding portion thereof comprises the olokizumab heavy chain V region and light chain V region.
  • the antibody is the full-length olokizumab antibody.
  • the anti-IL-6 antibody is a derivative of olokizumab.
  • the olokizumab derivative includes one or more amino acid substitutions in the olokizumab heavy and/or light chain V regions.
  • the olokizumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the olokizumab anti-IL-6 antibody, while retaining specificity for human IL-6.
  • the olokizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of olokizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the olokizumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of olokizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6).
  • the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of an antibody selected from the group consisting of: VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101.
  • the antibody or antigen-binding portion thereof comprises the heavy chain V region and light chain V region of an antibody selected from the group consisting of: VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101.
  • the antibody is a full-length antibody selected from the group consisting of: VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101.
  • the anti-IL-6 antibody is a derivative of an antibody selected from the group consisting of: VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101.
  • the IL-6 antagonist is an anti-IL-6 receptor (anti-IL-6R) antibody or antigen-binding fragment or derivative thereof.
  • the anti-IL-6R reduces the biological activity of IL-6 receptor.
  • the IL-6 antagonist is an anti-IL-6R monoclonal antibody. In some embodiments, the IL-6 antagonist is a polyclonal composition comprising a plurality of species of anti-IL-6R antibodies, each of the plurality having unique CDRs.
  • the anti-IL-6R antibody is a Fab, Fab′, F(ab′) 2 , Fv, scFv, (scFv) 2 , single chain antibody molecule, dual variable domain antibody, single variable domain antibody, linear antibody, or V domain antibody.
  • the anti-IL-6R antibody comprises a scaffold.
  • the scaffold is Fc, optionally human Fc.
  • the anti-IL-6R antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.
  • the anti-IL-6R antibody comprises a heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.
  • the IL-6 antagonist is immunoconjugate or fusion protein comprising an IL-6R antigen-binding fragment.
  • the antibody is bispecific or multispecific, with at least one of the antigen-binding portions having specificity for IL-6 receptor.
  • the antibody is fully human. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric and has non-human V regions and human C region domains. In some embodiments, the antibody is murine.
  • the anti-IL-6R antibody has a K D for binding human IL-6 receptor of less than 100 nM. In some embodiments, the anti-IL-6R antibody has a K D for binding human IL-6 receptor of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nM. In particular embodiments, the anti-IL-6R antibody has a K D for binding human IL-6 receptor of less than 5 nM, 4 nM, 3 nM, or 2 nM. In selected embodiments, the anti-IL-6R antibody has a K D for binding human IL-6 receptor of less than 1 nM, 750 pM, or 500 pM. In specific embodiments, the anti-IL-6R antibody has a K D for binding human IL-6 receptor of no more than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM.
  • the anti-IL-6R antibody has an elimination half-life following intravenous administration of at least 7 days. In certain embodiments, the anti-IL-6R antibody has an elimination half-life of at least 14 days, at least 21 days, or at least 30 days.
  • the anti-IL-6R antibody has a human IgG constant region with at least one amino acid substitution that extends serum half-life as compared to the unsubstituted human IgG constant domain.
  • the IgG constant domain comprises substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is a substitution with tyrosine, the amino acid substitution at amino acid residue 254 is a substitution with threonine, and the amino acid substitution at amino acid residue 256 is a substitution with glutamic acid (“YTE”).
  • YTE glutamic acid
  • the IgG constant domain comprises substitutions selected from T250Q/M428L (Hinton et al., J. Immunology 176:346-356 (2006)); N434A (Yeung et al., J. Immunology 182:7663-7671 (2009)); or T307A/E380A/N434A (Petkova et al., International Immunology, 18: 1759-1769 (2006)).
  • the elimination half-life of the anti-IL-6R antibody is increased by utilizing the FcRN-binding properties of human serum albumin.
  • the antibody is conjugated to albumin (Smith et al., Bioconjug. Chem., 12: 750-756 (2001)).
  • the anti-IL-6R antibody is fused to bacterial albumin-binding domains (Stork et al., Prot. Eng. Design Science 20: 569-76 (2007)).
  • the anti-IL-6R antibody is fused to an albumin-binding peptide (Nguygen et al., Prot Eng Design Sel 19: 291-297 (2006)).
  • the anti-IL-6R antibody is bispecific, with one specificity being to IL-6 receptor, and one specificity being to human serum albumin (Ablynx, WO 2006/122825 (bispecific Nanobody)).
  • the elimination half-life of the anti-IL-6R antibody is increased by PEGylation (Melmed et al., Nature Reviews Drug Discovery 7: 641-642 (2008)); by HPMA copolymer conjugation (Lu et al., Nature Biotechnology 17: 1101-1104 (1999)); by dextran conjugation ( Nuclear Medicine Communications, 16: 362-369 (1995)); by conjugation with homo-amino-acid polymers (HAPs; HAPylation) (Schlapschy et al., Prot Eng Design Sel 20: 273-284 (2007)); or by polysialylation (Constantinou et al., Bioconjug. Chem. 20: 924-931 (2009)).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of tocilizumab.
  • the antibody or antigen-binding portion thereof comprises the tocilizumab heavy chain V region and light chain V region.
  • the antibody is the full-length tocilizumab antibody.
  • the anti-IL-6R antibody is a derivative of tocilizumab.
  • the tocilizumab derivative includes one or more amino acid substitutions in the tocilizumab heavy and/or light chain V regions.
  • the tocilizumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the tocilizumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the tocilizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of tocilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the tocilizumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of tocilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of sarilumab.
  • the antibody or antigen-binding portion thereof comprises the sarilumab heavy chain V region and light chain V region.
  • the antibody is the full-length sarilumab antibody.
  • the anti-IL-6R antibody is a derivative of sarilumab.
  • the sarilumab derivative includes one or more amino acid substitutions in the sarilumab heavy and/or light chain V regions.
  • the sarilumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the sarilumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the sarilumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of sarilumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the sarilumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of sarilumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of vobarilizumab.
  • the antibody or antigen-binding portion thereof comprises the vobarilizumab heavy chain V region and light chain V region.
  • the antibody is the full-length vobarilizumab antibody.
  • the anti-IL-6R antibody is a derivative of vobarilizumab.
  • the vobarilizumab derivative includes one or more amino acid substitutions in the vobarilizumab heavy and/or light chain V regions.
  • the vobarilizumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original V H and/or V L of the vobarilizumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the vobarilizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the V H and V L domain of vobarilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the vobarilizumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of vobarilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the V H and/or V L CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL-6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (NovImmune), and an antibody described in US 2012/0225060.
  • the antibody or antigen-binding portion thereof comprises the heavy chain V region and light chain V region of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (NovImmune), and an antibody described in US 2012/0225060.
  • the antibody is a full-length selected from the group consisting of: SA237 (Roche), NI-1201 (NovImmune), and an antibody described in US 2012/0225060.
  • the anti-IL-6R antibody is a derivative of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (NovImmune), or an antibody described in US 2012/0225060.
  • the IL-6 antagonist is an antibody specific for the complex of IL-6 and IL-6R.
  • the antibody has the six CDRs of an antibody selected from those described in US 2011/0002936, which is incorporated herein by reference in its entirety.
  • the IL-6 antagonist is an inhibitor of the JAK signaling pathway.
  • the JAK inhibitor is a JAK1-specific inhibitor.
  • the JAK inhibitor is a JAK3-specific inhibitor.
  • the JAK inhibitor is a pan-JAK inhibitor.
  • the JAK inhibitor is selected from the group consisting of tofacitinib (Xeljanz), decernotinib, ruxolitinib, upadacitinib, baricitinib, filgotinib, lestaurtinib, pacritinib, peficitinib, INCB-039110, ABT-494, INCB-047986 and AC-410.
  • the IL-6 antagonist is a STAT3 inhibitor.
  • the inhibitor is AZD9150 (AstraZeneca, Isis Pharmaceuticals), a STAT3 antisense molecule.
  • the IL-6 antagonist is an antagonist peptide.
  • the IL-6 antagonist is C326 (an IL-6 inhibitor by Avidia, also known as ANIG220), or FE301, a recombinant protein inhibitor of IL-6 (Ferring International Center S.A., Conaris Research Institute AG).
  • the anti-IL-6 antagonist comprises soluble gp130, FE301 (Conaris/Ferring).
  • IL-6 antagonists used in the methods described herein can be formulated in any appropriate pharmaceutical composition for administration by any suitable route of administration.
  • suitable routes of administration include, but are not limited to, the intravitreal, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes.
  • the pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety.
  • the IL-6 antagonist is administered at a dose sufficient to reduce inflammation without causing immune suppression.
  • antibody, antigen-binding fragments, and peptide IL-6 antagonists are administered parenterally.
  • the IL-6 antagonist is administered intravenously. In certain intravenous embodiments, the IL-6 antagonist is administered as a bolus. In certain intravenous embodiments, the IL-6 antagonist is administered as an infusion. In certain intravenous embodiments, the IL-6 antagonist is administered as a bolus followed by infusion.
  • the IL-6 antagonist is administered subcutaneously.
  • the antibody, antigen-binding fragment, or peptide IL-6 antagonist is administered in a dose that is independent of patient weight or surface area (flat dose).
  • the intravenous flat dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg. In some embodiments, the intravenous flat dose is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the intravenous flat dose is 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, the intravenous flat dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the intravenous flat dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg.
  • the intravenous flat dose is 200 mg, 300 mg, 400 mg, or 500 mg. In some embodiments, the intravenous flat dose is 0.1-1 mg, 1-10 mg, 10-15 mg, 15-20 mg, 20-30 mg, 30-40 mg, or 40-50 mg. In some embodiments, the intravenous flat dose is 1-50 mg, 50-100 mg, or 100 mg -500 mg.
  • the subcutaneous flat dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg. In some embodiments, the subcutaneous flat dose is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the subcutaneous flat dose is 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, the subcutaneous flat dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the subcutaneous flat dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg.
  • the subcutaneous flat dose is 200 mg, 300 mg, 400 mg, or 500 mg. In some embodiments, the subcutaneous flat dose is 0.1-1 mg, 1-10 mg, 10-15 mg, 15-20 mg, 20-30 mg, 30-40 mg, or 40-50 mg. In some embodiments, the subcutaneous flat dose is 1-50 mg, 50-100 mg, or 100 mg -500 mg.
  • the antibody, antigen-binding fragment, or peptide IL-6 antagonist is administered as a patient weight-based dose.
  • the antagonist is administered at an intravenous dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg or 0.1 mg/kg. In some embodiments, the antagonist is administered at an intravenous dose of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg or 1.0 mg/kg. In some embodiments, the antagonist is administered at an intravenous dose of 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg.
  • the antagonist is administered at a subcutaneous dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg or 0.1 mg/kg. In some embodiments, the antagonist is administered at a subcutaneous dose of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg or 1.0 mg/kg. In some embodiments, the antagonist is administered at a subcutaneous dose of 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg.
  • the IL-6 antagonist is administered once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once a month. In various subcutaneous embodiments, the IL-6 antagonist is administered once every 14 days, once every 28 days, once a month, once every two months (every other month), or once every three months.
  • small molecule JAK inhibitors and STAT inhibitors are administered orally.
  • the inhibitor is administered once or twice a day at an oral dose of 0.1-1 mg, 1-10 mg, 10-20 mg, 20-30 mg, 30-40 mg, or 40-50 mg. In some embodiments, the inhibitor is administered once or twice a day at a dose of 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg. In some embodiments, the inhibitor is administered at a dose of 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg PO once or twice a day. In some embodiments, the inhibitor is administered at a dose of 75 mg or 100 mg PO once or twice a day.
  • the IL-6 antagonist is administered at a monthly equivalent dose that is less than the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.
  • “Monthly equivalent dose” is the calculated total dose administered per month, regardless of dose amount and dosage schedule.
  • the IL-6 antagonist is administered at a monthly equivalent dose no more than 50% of a monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In various embodiments, the IL-6 antagonist is administered at a monthly equivalent dose no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of a monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose no more than 45% of a monthly equivalent dose for treating rheumatoid arthritis.
  • the IL-6 antagonist is administered at a monthly equivalent dose no more than 40% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose no more than 30% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose no more than 25% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose no more than 20% of a monthly equivalent dose for treating rheumatoid arthritis.
  • the IL-6 antagonist is administered at a monthly equivalent dose no more than 15% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose no more than 10% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose no more than 5% of a monthly equivalent dose for treating rheumatoid arthritis.
  • the IL-6 antagonist is administered at a monthly equivalent dose about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of a monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.
  • the IL-6 antagonist is administered at a monthly equivalent dose about 50% of a monthly equivalent dose for treating rheumatoid arthritis.
  • the IL-6 antagonist is administered at a monthly equivalent dose about 40% of a monthly equivalent dose for treating rheumatoid arthritis.
  • the IL-6 antagonist is administered at a monthly equivalent dose about 30% of a monthly equivalent dose for treating rheumatoid arthritis.
  • the IL-6 antagonist is administered at a monthly equivalent dose about 25% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose about 20% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose about 15% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose about 10% of a monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose about 5% of a monthly equivalent dose for treating rheumatoid arthritis.
  • the IL-6 antagonist is the COR-001 antibody.
  • COR-001 is administered intravenously at a monthly equivalent dose of 0.5-50 mg, such as 0.5-1 mg, 0.5-2 mg, 0.5-5 mg, 0.5-10 mg, 0.5-20 mg, 0.5-30 mg, 0.5-40 mg, 1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 20-30 mg, 20-40 mg, 20-50 mg, 30-40 mg, 30-50 mg, or 40-50 mg.
  • COR-001 is administered intravenously at a monthly equivalent dose of 2-40 mg.
  • COR-001 is administered intravenously at a monthly equivalent dose of about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg.
  • COR-001 is administered intravenously at a monthly equivalent dose of about 1 mg.
  • COR-001 is administered intravenously at a monthly equivalent dose of about 2 mg.
  • COR-001 is administered intravenously at a monthly equivalent dose of about 3 mg.
  • COR-001 is administered intravenously at a monthly equivalent dose of about 4 mg.
  • COR-001 is administered intravenously at a monthly equivalent dose of about 5 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 6 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 10 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 12 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 15 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 20 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of about 40 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of 1-100 mg, such as 1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 1-70 mg, 1-100 mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg, 2-70 mg, 2-100 mg, 3-5 mg, 3-10 mg, 3-20 mg, 3-30 mg, 3-40 mg, 3-50 mg, 3-70 mg, 3-100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 5-70 mg, 5-100 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-70 mg, 10-100 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-70 mg, 20-100 mg, 30-40 mg, 30-50 mg, 30-70 mg, 30-100 mg, or 40-100 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of 3-70 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 70 mg, or 100 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of about 1 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of about 2 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of about 3 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of about 4 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of about 5 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 6 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 10 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 12 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 15 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 17 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 20 mg.
  • COR-001 is administered subcutaneously at a monthly equivalent dose of about 35 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 40 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 70 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of about 100 mg.
  • the IL-6 antagonist is siltuximab.
  • siltuximab is administered intravenously at a monthly equivalent dose of 10-500 mg, such as 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-100 mg, 10-150 mg, 10-200 mg, 10-300 mg, 10-400 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-100 mg, 20-150 mg, 20-200 mg, 20-300 mg, 20-400 mg, 20-500 mg, 30-40 mg, 30-50 mg, 30-100 mg, 30-150 mg, 30-200 mg, 30-300 mg, 30-400 mg, 30-500 mg, 40-50 mg, 40-100 mg, 40-150 mg, 40-200 mg, 40-250 mg, 40-300 mg, 40-400 mg, 40-500 mg, 50-100 mg, 50-150 mg, 50-200 mg, 50-300 mg, 50-400 mg, 50-500 mg, 100-150 mg, 100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 150-
  • 10-500 mg such as
  • siltuximab is administered intravenously at a monthly equivalent dose of 50-500 mg. In various embodiments, siltuximab is administered intravenously at a monthly equivalent dose of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 500 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of about 50 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of about 100 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of about 150 mg.
  • siltuximab is administered intravenously at a monthly equivalent dose of about 200 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of about 300 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of about 500 mg.
  • siltuximab is administered subcutaneously at a monthly equivalent dose of 50-1000 mg, such as 50-80 mg, 50-100 mg, 50-160 mg, 50-200 mg, 50-240 mg, 50-320 mg, 50-480 mg, 50-800 mg, 80-100 mg, 80-160 mg, 80-200 mg, 80-240 mg, 80-320 mg, 80-480 mg, 80-800 mg, 80-1000 mg, 100-160 mg, 100-200 mg, 100-240 mg, 100-320 mg, 100-480 mg, 100-800 mg, 100-1000 mg, 160-200 mg, 160-240 mg, 160-320 mg, 160-480 mg, 160-800 mg, 160-1000 mg, 200-240 mg, 200-320 mg, 200-480 mg, 200-800 mg, 200-1000 mg, 240-320 mg, 240-480 mg, 200-800 mg, 200-1000 mg, 240-320 mg, 240-480 mg, 240-800 mg, 240-1000 mg, 320-480 mg, 320-800 mg,
  • siltuximab is administered subcutaneously at a monthly equivalent dose of 80-800 mg. In various embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 50 mg, 80 mg. 100 mg, 160 mg, 240 mg. 320 mg, 480 mg. 800 mg, or 1000 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 50 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 80 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 100 mg.
  • siltuximab is administered subcutaneously at a monthly equivalent dose of about 160 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 240 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 320 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 480 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 800 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of about 1000 mg.
  • the IL-6 antagonist is gerilimzumab.
  • gerilimzumab is administered intravenously at a monthly equivalent dose of 0.05-2 mg, such as 0.05-0.075 mg, 0.05-0.1 mg, 0.05-0.12 mg, 0.05-0.3 mg, 0.05-0.6 mg, 0.05-0.9 mg, 0.05-1.8 mg, 0.075-0.1 mg, 0.075-0.12 mg, 0.075-0.3 mg, 0.075-0.6 mg, 0.075-0.9 mg, 0.075-1.8 mg, 0.075-2 mg, 0.1-0.12 mg, 0.1-0.3 mg, 0.1-0.6 mg, 0.1-0.9 mg, 0.1-1.8 mg, 0.1-2 mg, 0.12-0.3 mg, 0.12-0.6 mg, 0.12-0.9 mg, 0.12-1.8 mg, 0.12-2 mg, 0.3-0.6 mg, 0.3-0.9 mg, 0.3-1.8 mg, 0.3-2 mg, 0.6-0.9 mg, 0.6-1.8 mg, 0.6-2 mg, 0.9-1.8 mg, 0.9-2 mg, or
  • gerilimzumab is administered intravenously at a monthly equivalent dose of 0.075-1.8 mg. In various embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.05 mg, 0.075 mg, 0.1 mg, 0.12 mg, 0.3 mg, 0.6 mg, 0.9 mg, 1.8 mg, or 2 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.05 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.075 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.1 mg.
  • gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.12 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.3 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.6 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 0.9 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 1.8 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of about 2 mg.
  • gerilimzumab is administered subcutaneously at a monthly equivalent dose of 0.1-5 mg, such as 0.1-0.125 mg, 0.1-0.15 mg, 0.1-0.2 mg, 0.1-0.5 mg, 0.1-1 mg, 0.1-1.5 mg, 0.1-2 mg, 0.1-3 mg, 0.1-4 mg, 0.125-0.15 mg, 0.125-0.2 mg, 0.125-0.5 mg, 0.125-1 mg, 0.125-1.5 mg, 0.125-2 mg, 0.125-3 mg, 0.125-4 mg, 0.125-5 mg, 0.15-0.2 mg, 0.15-0.5 mg, 0.15-1 mg, 0.15-1.5 mg, 0.15-2 mg, 0.15-3 mg, 0.15-4 mg, 0.15-5 mg, 0.2-0.5 mg, 0.2-1 mg, 0.2-1.5 mg, 0.2-2 mg, 0.2-3 mg, 0.2-4 mg, 0.2-5 mg, 0.5-1 mg, 0.5-1.5 mg, 0.5-2 mg, 0.5-3 mg, 0.5-4 mg, 0.5-5 mg, 1-1.5 mg, 1-2 mg, 1-3 mg, 1-4 mg, 1-5 mg,
  • gerilimzumab is administered subcutaneously at a monthly equivalent dose of 0.125-3 mg. In various embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 0.1 mg, 0.125 mg, 0.15 mg, 0.2 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, or 5 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 0.125 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 0.2 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 0.5 mg.
  • gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 1 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 1.5 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of about 3 mg.
  • the IL-6 antagonist is sirukumab.
  • sirukumab is administered intravenously at a monthly equivalent dose of 1-80 mg, such as 1-1.5 mg, 1-3 mg, 1-6 mg, 1-12 mg, 1-36 mg, 1-60 mg, 1.5-3 mg, 1.5-6 mg, 1.5-12 mg, 1.5-36 mg, 1.5-60 mg, 1.5-80 mg, 3-6 mg, 3-12 mg, 3-36 mg, 3-60 mg, 3-80 mg, 6-12 mg, 6-36 mg, 6-60 mg, 6-80 mg, 12-36 mg, 12-60 mg, 12-80 mg, 36-60 mg, 36-80 mg, or 60-80 mg.
  • sirukumab is administered intravenously at a monthly equivalent dose of 1.5-60 mg.
  • sirukumab is administered intravenously at a monthly equivalent dose of about 1 mg, 1.5 mg, 3 mg, 6 mg, 12 mg, 36 mg, 60 mg, or 80 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 1 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 1.5 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 3 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 6 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 12 mg.
  • sirukumab is administered intravenously at a monthly equivalent dose of about 36 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 60 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of about 80 mg.
  • sirukumab is administered subcutaneously at a monthly equivalent dose of 1-100 mg, such as 1-2.5 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 1-60 mg, 2.5-5 mg, 2.5-10 mg, 2.5-20 mg, 2.5-30 mg, 2.5-40 mg, 2.5-50 mg, 2.5-60 mg, 2.5-100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 5-60 mg, 5-100 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-60 mg, 10-100 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-60 mg, 20-100 mg, 30-40 mg, 30-50 mg, 30-60 mg, 30-100 mg, 40-50 mg, 40-60 mg, 40-100 mg, 50-60 mg, 50-100 mg, or 60-100 mg.
  • 1-100 mg such as 1-2.5 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 1-60 mg, 2.5-5 mg, 2.5-10 mg, 2.5
  • sirukumab is administered subcutaneously at a monthly equivalent dose of 2.5-100 mg. In various embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 100 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 2.5 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 5 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 10 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 20 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 60 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of about 100 mg.
  • the IL-6 antagonist is clazakizumab.
  • clazakizumab is administered intravenously at a monthly equivalent dose of 1-80 mg, such as 1-3 mg, 1-6 mg, 1-12 mg, 1-24 mg, 1-36 mg, 1-60 mg, 3-6 mg, 3-12 mg, 3-24 mg, 3-36 mg, 3-60 mg, 3-80 mg, 6-12 mg, 6-24 mg, 6-36 mg, 6-60 mg, 6-80 mg, 12-24 mg, 12-36 mg, 12-60 mg, 12-80 mg, 24-36 mg, 24-60 mg, 24-80 mg, 36-60 mg, 36-80 mg, or 60-80 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of 3-60 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of about 1 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, 60 mg or 80 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of about 1 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of about 3 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of about 6 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of about 12 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of about 24 mg.
  • clazakizumab is administered intravenously at a monthly equivalent dose of about 36 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of about 60 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of about 80 mg.
  • clazakizumab is administered subcutaneously at a monthly equivalent dose of 1-100 mg, such as 1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 1-60 mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg, 2-60 mg, 2-100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 5-60 mg, 5-100 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-60 mg, 10-100 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-60 mg, 20-100 mg, 30-40 mg, 30-50 mg, 30-60 mg, 30-100 mg, 40-50 mg, 40-60 mg, 40-100 mg, 50-60 mg, 50-100 mg, or 60-100 mg.
  • clazakizumab is administered subcutaneously at a monthly equivalent dose of 5-100 mg. In various embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 100 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 5 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 10 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 20 mg.
  • clazakizumab is administered subcutaneously at a monthly equivalent dose of about 40 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 60 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of about 100 mg.
  • the IL-6 antagonist is olokizumab.
  • olokizumab is administered intravenously at a monthly equivalent dose of 1-80 mg, such as 1-1.8 mg, 1-3.6 mg, 1-9 mg, 1-18 mg, 1-45 mg, 1-60 mg, 1.8-3.6 mg, 1.8-9 mg, 1.8-18 mg, 1.8-45 mg, 1.8-60 mg, 1.8-80 mg, 3.6-9 mg, 3.6-18 mg, 3.6-45 mg, 3.6-60 mg, 3.6-80 mg, 9-18 mg, 9-45 mg, 9-60 mg, 9-80 mg, 18-45 mg, 18-60 mg, 18-80 mg, 45-60 mg, 45-80 mg, or 60-80 mg.
  • olokizumab is administered intravenously at a monthly equivalent dose of 1.8-60 mg. In various embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 1 mg, 1.8 mg, 3.6 mg, 9 mg, 18 mg. 45 mg, 60 mg, or 80 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 1 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 1.8 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 3.6 mg.
  • olokizumab is administered intravenously at a monthly equivalent dose of about 9 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 18 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 45 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 60 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of about 80 mg.
  • olokizumab is administered subcutaneously at a monthly equivalent dose of 1-100 mg, such as 1-3 mg, 1-6 mg, 1-10 mg, 1-15 mg, 1-20 mg, 1-30 mg, 1-50 mg, 1-72 mg, 3-6 mg, 3-10 mg, 3-15 mg, 3-20 mg, 3-30 mg, 3-50 mg, 3-72 mg, 3-100 mg, 6-10 mg, 6-15 mg, 6-20 mg, 6-30 mg, 6-50 mg, 6-72 mg, 6-100 mg, 10-15 mg, 10-20 mg, 10-30 mg, 10-50 mg, 10-72 mg, 10-100 mg, 15-20 mg, 15-30 mg, 15-50 mg, 15-72 mg, 15-100 mg, 20-30 mg, 20-50 mg, 20-72 mg, 20-100 mg, 30-50 mg, 30-72 mg, 30-100 mg, 50-72 mg, 50-100 mg, or 72-100 mg.
  • 1-100 mg such as 1-3 mg, 1-6 mg, 1-10 mg, 1-15 mg, 1-20 mg, 1-30 mg, 1-50 mg, 1-72 mg, 3-6 mg, 3-10 mg
  • olokizumab is administered subcutaneously at a monthly equivalent dose of 3-100 mg. In various embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 1 mg, 3 mg, 6 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, 72 mg, or 100 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 3 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 6 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 15 mg.
  • olokizumab is administered subcutaneously at a monthly equivalent dose of about 30 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 72 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of about 100 mg.
  • the IL-6 antagonist is tocilizumab.
  • tocilizumab is administered intravenously at a monthly equivalent dose of 10-500 mg, such as 10-20 mg, 10-50 mg, 10-100 mg, 10-150 mg, 10-200 mg, 10-250 mg, 10-300 mg, 10-350 mg, 10-400 mg, 20-50 mg, 20-100 mg, 20-150 mg, 20-200 mg, 20-250 mg, 20-300 mg, 20-350 mg, 20-400 mg, 20-500 mg, 50-100 mg, 50-150 mg, 50-200 mg, 50-250 mg, 50-300 mg, 50-350 mg, 50-400 mg, 50-500 mg, 100-150 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 100-400 mg, 100-500 mg, 150-200 mg, 150-250 mg, 150-300 mg, 150-350 mg, 150-400 mg, 150-500 mg, 200-250 mg, 200-300 mg, 200-350 mg, 200-400 mg, 200-500 mg,
  • tocilizumab is administered intravenously at a monthly equivalent dose of 50-500 mg. In various embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 500 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of about 50 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of about 100 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of about 150 mg.
  • tocilizumab is administered intravenously at a monthly equivalent dose of about 250 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of about 350 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of about 500 mg.
  • tocilizumab is administered subcutaneously at a monthly equivalent dose of 50-1000 mg, such 50-80 mg, 50-160 mg, 50-240 mg, 50-400 mg, 50-560 mg, 50-800 mg, 80-160 mg, 80-240 mg, 80-400 mg, 80-560 mg, 80-800 mg, 80-1000 mg, 160-240 mg, 160-400 mg, 160-560, 160-800 mg, 160-1000 mg, 240-400 mg, 240-560 mg, 240-800 mg, 240-1000 mg, 400-560 mg, 400-800 mg, 400-1000 mg, 560-800 mg, 560-1000 mg, or 800-100 mg.
  • 50-1000 mg such 50-80 mg, 50-160 mg, 50-240 mg, 50-400 mg, 50-560 mg, 50-800 mg, 80-160 mg, 80-240 mg, 80-400 mg, 80-560 mg, 80-800 mg, 80-1000 mg, 160-240 mg, 160-400 mg, 160-560, 160-800 mg, 160-1000 mg, 240
  • tocilizumab is administered subcutaneously at a monthly equivalent dose of 80-800 mg. In various embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 50 mg, 80 mg, 160 mg, 240 mg, 400 mg, 560 mg, 800 mg, or 1000 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 50 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 80 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 160 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 240 mg.
  • tocilizumab is administered subcutaneously at a monthly equivalent dose of about 400 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 560 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 800 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of about 1000 mg.
  • the IL-6 antagonist is sarilumab.
  • sarilumab is administered intravenously at a monthly equivalent dose of 10-150 mg, such as 10-12 mg, 10-24 mg, 10-48 mg, 10-60 mg, 10-72 mg, 10-120 mg, 12-24 mg, 12-48 mg, 12-60 mg, 12-72 mg, 12-120 mg, 12-150 mg, 24-48 mg, 24-60 mg, 24-72 mg, 24-120 mg, 24-150 mg, 48-60 mg, 48-72 mg, 48-120 mg, 48-150 mg, 60-72 mg, 60-120 mg, 60-150 mg, 72-120 mg, 72-150 mg, or 120-150 mg.
  • sarilumab is administered intravenously at a monthly equivalent dose of 12-120 mg. In various embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 10 mg, 12 mg, 24 mg, 48 mg, 60 mg, 72 mg, 120 mg, or 150 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 10 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 12 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 24 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 48 mg.
  • sarilumab is administered intravenously at a monthly equivalent dose of 60 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 72 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 120 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 150 mg.
  • sarilumab is administered subcutaneously at a monthly equivalent dose of 10-200 mg, such as 10-20 mg, 10-40 mg, 10-60 mg, 10-80 mg, 10-100 mg, 10-120 mg, 20-40 mg, 20-60 mg, 20-80 mg, 20-100 mg, 20-120 mg, 20-200 mg, 40-60 mg, 40-80 mg, 40-100 mg, 40-120 mg, 40-200 mg, 60-80 mg, 60-100 mg, 60-120 mg, mg, 60-200 mg, 80-100 mg, 80-120 mg, 80-200 mg, 100-120 mg, 100-200 mg, or 120-200 mg.
  • sarilumab is administered subcutaneously at a monthly equivalent dose of 20-200 mg.
  • sarilumab is administered subcutaneously at a monthly equivalent dose of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, or 200 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 20 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 40 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 80 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 100 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 120 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of about 200 mg.
  • the IL-6 antagonist is vobarilizumab.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of 2-150 mg, such as 2-4 mg, 2-6 mg, 2-30 mg, 2-60 mg, 2-84 mg, 2-120 mg, 4-6 mg, 4-30 mg, 4-60 mg, 4-84 mg, 4-120 mg, 4-150 mg, 6-30 mg, 6-60 mg, 6-84 mg, 6-120 mg, 6-150 mg, 30-60 mg, 30-84 mg, 30-120 mg, 30-150 mg, 60-84 mg, 60-120 mg, 60-150 mg, 84-120 mg, 84-150 mg, or 120-150 mg.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of 4-120 mg. In various embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 2 mg, 4 mg, 6 mg, 30 mg, 60 mg, 84 mg, 120 mg, or 150 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 2 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 4 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 6 mg.
  • vobarilizumab is administered intravenously at a monthly equivalent dose of about 30 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 60 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 84 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 120 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of about 150 mg.
  • vobarilizumab is administered subcutaneously at a monthly equivalent dose of 5-200 mg, such as 5-7 mg, 5-10 mg, 5-20 mg, 5-50 mg, 5-70 mg, 5-100 mg, 5-140 mg, 7-10 mg, 7-20 mg, 7-50 mg, 7-70 mg, 7-100 mg, 7-140 mg, 7-200 mg, 10-20 mg, 10-50 mg, 10-70 mg, 10-100 mg, 10-140 mg, 10-200 mg, 20-50 mg, 20-70 mg, 20-100 mg, 20-140 mg, 20-200 mg, 50-70 mg, 50-100 mg, 50-140 mg, 50-200 mg, 70-100 mg, 70-140 mg, 70-200 mg, 100-140 mg, 100-200 mg, or 140-200 mg.
  • 5-200 mg such as 5-7 mg, 5-10 mg, 5-20 mg, 5-50 mg, 5-70 mg, 5-100 mg, 5-140 mg, 7-10 mg, 7-20 mg, 7-50 mg, 7-70 mg, 7-100 mg, 7-140 mg, 7-200 mg, 10-20
  • vobarilizumab is administered subcutaneously at a monthly equivalent dose of 7-200 mg. In various embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 5 mg, 7 mg, 10 mg, 20 mg, 40 mg, 50 mg, 70 mg, 100 mg, 140 mg, or 200 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 7 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 10 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 50 mg.
  • vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 100 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 140 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of about 200 mg.
  • COR-001 is a human IgG1, kappa antibody directed against interleukin-6 (IL-6). COR-001 contains a “YTE” mutation in its Fc region. The sequence and other features of COR-001 are described in Chapter 2.7.1.1 above.
  • the study was a randomized, double-blind, placebo-controlled trial designed to evaluate the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of COR-001 (MEDI5117) or placebo administered to sequential cohorts of hemodialysis patients.
  • stage 5 chronic kidney disease (CK D -5) on hemodialysis, positive for TMPRSS6 736A genotype (major allele), IL-6 level greater than 4 pg/mL, and erythropoietic resistive index greater than 8.
  • Ten hemodialysis patients were randomized to COR-001 or placebo within each dosing cohort.
  • the first 2 (sentinel) patients in that cohort were randomized first and the remaining patients were randomized at least 48 hours later, in a 7:1 ratio of COR-001 to placebo.
  • the final ratio of patients treated with COR-001 vs. placebo were 8:2 in each cohort of 10 patients.
  • the maximum tolerated dose (MTD) assessment was based on safety data from Weeks 1 to 3. If more than 2 of 8 active patients in a cohort experienced a dose-limiting toxicity (DLT), the MTD was considered to have been exceeded.
  • DLT dose-limiting toxicity
  • COR-001 The Dose Escalation Schematic is shown in FIG. 1 .
  • COR-001 was administered as an intravenous infusion, started any time before the last 1 hour of the dialysis treatment.
  • the COR-001 dose regimens are shown in Table 1 below.
  • the total study duration for an individual patient was approximately 9 months, excluding the screening period of up to 4 weeks.
  • the study included a treatment period of 12 weeks (Week 1 through Week 12), a safety follow-up period of 12 weeks (Week 13 through Week 24), and an extended follow-up period of 10 weeks (Week 25 through Week 35).
  • Interim study-collected data were summarized by treatment group for the appropriate analysis population, using descriptive statistics.
  • Descriptive statistics for continuous variables included number of patients (n), mean, standard deviation (SD), median, quartiles (Q1 and Q3), minimum (min) and maximum (max) values.
  • Analysis of categorical variables included frequency and percentages.
  • hsCRP high-sensitivity C-reactive protein
  • ANC absolute neutrophil count
  • TSAT transferrin saturation
  • albumin erythropoietic resistive index
  • handgrip handgrip
  • NT-proBNP cardiac MRI
  • CRP C-reactive protein
  • hsCRP high-sensitivity C-reactive protein
  • the percentages of patients with post-treatment average hsCRP ⁇ 2 mg/L at Week 12 were 44%, 62%, and 85% in the 2 mg dose regimen, 6 mg dose regimen, and 20 mg dose regimen groups, respectively, as compared to 14% in the placebo group.
  • the hsCRP responder analysis shows that COR-001 (anti-IL-6) has a superior effect on hsCRP than has been reported for canakinumab (anti-IL1 ⁇ ) in the CANTOS trial.
  • COR-001 improved a primary indicator of anemia, hemoglobin levels.
  • the hemoglobin responder analysis indicated a dose-dependent hemoglobin responder rate of COR-001 treatment ( FIG. 4 ).
  • COR-001 decreased the level of the N-terminal prohormone of brain natriuretic peptide (NT-proBNP). The result indicates that treatment of COR-001 can reduce heart failure.
  • Immune suppression can be measured by neutrophil counts. The effect of COR-001 on neutrophil counts was determined.
  • COR-001 treatment at doses of 2 mg, 6 mg, and 20 mg can reduce inflammation without inducing immune suppression in patients with stage 5 chronic kidney disease (CK D -5) on dialysis, whereas the absolute neutrophil count was not decreased significantly in patients treated with COR-001.
  • COR-001 reduced CRP in a dose-dependent matter.
  • COR-001 increased hemoglobin level in these patients.
  • COR-001 decreased the biomarkers of heart failure NT-proBNP.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
US16/240,670 2018-01-05 2019-01-04 Methods for treating il-6 mediated inflammation without immunosuppression Abandoned US20190241650A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US16/240,670 US20190241650A1 (en) 2018-01-05 2019-01-04 Methods for treating il-6 mediated inflammation without immunosuppression
US16/396,378 US11384143B2 (en) 2018-01-05 2019-04-26 Methods for treating IL-6 mediated inflammation without immunosuppression
US17/708,660 US20220227856A1 (en) 2018-01-05 2022-03-30 Methods for treating il-6 mediated inflammation without immunosuppression
US17/991,880 US20230090473A1 (en) 2018-01-05 2022-11-22 Methods for treating il-6 mediated inflammation without immunosuppression

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862614134P 2018-01-05 2018-01-05
US16/240,670 US20190241650A1 (en) 2018-01-05 2019-01-04 Methods for treating il-6 mediated inflammation without immunosuppression

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/396,378 Continuation US11384143B2 (en) 2018-01-05 2019-04-26 Methods for treating IL-6 mediated inflammation without immunosuppression

Publications (1)

Publication Number Publication Date
US20190241650A1 true US20190241650A1 (en) 2019-08-08

Family

ID=67143789

Family Applications (4)

Application Number Title Priority Date Filing Date
US16/240,670 Abandoned US20190241650A1 (en) 2018-01-05 2019-01-04 Methods for treating il-6 mediated inflammation without immunosuppression
US16/396,378 Active US11384143B2 (en) 2018-01-05 2019-04-26 Methods for treating IL-6 mediated inflammation without immunosuppression
US17/708,660 Pending US20220227856A1 (en) 2018-01-05 2022-03-30 Methods for treating il-6 mediated inflammation without immunosuppression
US17/991,880 Pending US20230090473A1 (en) 2018-01-05 2022-11-22 Methods for treating il-6 mediated inflammation without immunosuppression

Family Applications After (3)

Application Number Title Priority Date Filing Date
US16/396,378 Active US11384143B2 (en) 2018-01-05 2019-04-26 Methods for treating IL-6 mediated inflammation without immunosuppression
US17/708,660 Pending US20220227856A1 (en) 2018-01-05 2022-03-30 Methods for treating il-6 mediated inflammation without immunosuppression
US17/991,880 Pending US20230090473A1 (en) 2018-01-05 2022-11-22 Methods for treating il-6 mediated inflammation without immunosuppression

Country Status (20)

Country Link
US (4) US20190241650A1 (he)
EP (1) EP3735421A4 (he)
JP (2) JP7395479B2 (he)
KR (2) KR20200116089A (he)
CN (1) CN111787950A (he)
AU (1) AU2019205936B2 (he)
BR (1) BR112020013519A2 (he)
CA (1) CA3087699A1 (he)
CL (2) CL2020001790A1 (he)
CO (1) CO2020009510A2 (he)
EA (1) EA202091640A1 (he)
IL (1) IL275696A (he)
MA (1) MA51584A (he)
MX (1) MX2020006882A (he)
PE (1) PE20211196A1 (he)
PH (1) PH12020551040A1 (he)
RU (1) RU2020125805A (he)
SG (1) SG11202006157VA (he)
WO (1) WO2019136312A1 (he)
ZA (1) ZA202004074B (he)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020223565A1 (en) 2019-05-01 2020-11-05 Corvidia Therapeutics, Inc. Anti-il-6 antibody formulation
US11203636B2 (en) 2017-02-01 2021-12-21 Yale University Treatment of existing left ventricular heart failure
CN114206442A (zh) * 2019-01-31 2022-03-18 赛诺菲生物技术公司 用于治疗幼年特发性关节炎的抗il-6受体抗体
US11384143B2 (en) 2018-01-05 2022-07-12 Novo Nordisk A/S Methods for treating IL-6 mediated inflammation without immunosuppression

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115666704A (zh) 2019-12-13 2023-01-31 比奥拉治疗股份有限公司 用于将治疗剂递送至胃肠道的可摄取装置
AR122933A1 (es) * 2020-07-10 2022-10-19 Novo Nordisk As Métodos para tratar la enfermedad cardiovascular
WO2022167916A1 (en) * 2021-02-03 2022-08-11 Novartis Ag Use of il-1b binding antibodies for treating neuroinflammatory disorders
JP7132665B1 (ja) * 2022-02-25 2022-09-07 株式会社 バイオミメティクスシンパシーズ 腫瘍を縮小又は消失させるための組成物

Family Cites Families (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399429A1 (en) 1989-05-22 1990-11-28 Toray Industries, Inc. Anti-human interleukin-6 monoclonal antibody
JP2881311B2 (ja) 1989-07-28 1999-04-12 味の素株式会社 抗ヒトｂｃｄｆモノクローナル抗体及びそれを用いたヒトｂｃｄｆの定量法
AU6808194A (en) 1993-05-31 1994-12-20 Chugai Seiyaku Kabushiki Kaisha Reconstructed human antibody against human interleukin-6
US5888510A (en) 1993-07-21 1999-03-30 Chugai Seiyaku Kabushiki Kaisha Chronic rheumatoid arthritis therapy containing IL-6 antagonist as effective component
DE69534075T2 (de) 1994-06-07 2005-07-21 Chugai Seiyaku K.K. Vorbeugungs- und heilmittel für erkrankungen, die durch fibrin- oder thrombusbildung hervorgerufen werden
US8017121B2 (en) 1994-06-30 2011-09-13 Chugai Seiyaku Kabushika Kaisha Chronic rheumatoid arthritis therapy containing IL-6 antagonist as effective component
JPH1066582A (ja) 1996-08-27 1998-03-10 Tosoh Corp Ｉｌ−６のヘリックスｄ領域を認識する抗体の遺伝子断片等
US6723319B1 (en) 1998-03-17 2004-04-20 Chugai Seiyaku Kabushiki Kaisha Method of treating inflammatory intestinal diseases containing as the ingredient IL-6 receptors antibodies
US6395273B1 (en) 1998-06-10 2002-05-28 Promega Corporation Prevention and treatment of inflammatory bowel disease
CN1550235A (zh) * 1999-04-29 2004-12-01 ŵ��Ų�ڿ˹�˾ 结合肝素的拮抗剂在缓激肽释放的抑制中的应用
US7163681B2 (en) 2000-08-07 2007-01-16 Centocor, Inc. Anti-integrin antibodies, compositions, methods and uses
WO2002036164A1 (fr) 2000-10-27 2002-05-10 Chugai Seiyaku Kabushiki Kaisha Agent abaissant le taux sanguin de vegf contenant un antagoniste de il-6 en tant que principe actif
DE60143544D1 (de) 2000-12-12 2011-01-05 Medimmune Llc Moleküle mit längeren halbwertszeiten, zusammensetzungen und deren verwendung
US7658921B2 (en) 2000-12-12 2010-02-09 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
WO2003002064A2 (en) 2001-06-28 2003-01-09 Essential Therapeutics, Inc. Fused pyrimidine dhfr inhibitors as antibacterials
BRPI0214168B8 (pt) 2001-11-14 2021-05-25 Centocor Inc anticorpos anti-il-6, moléculas de ácido nucleico codificando os mesmos, vetores compreendendo as referidas moléculas, composições e formulações compreendendo os referidos anticorpos, bem como métodos de produção dos mesmos
CA2467521A1 (en) 2001-11-16 2003-07-10 Human Genome Sciences, Inc. Antibodies that immunospecifically bind to blys
FR2833011B1 (fr) 2001-12-04 2004-10-29 Univ Claude Bernard Lyon Nouvelle proteine a activite inhibitrice de l'il-6
EP2135879A3 (en) 2002-06-28 2010-06-23 Domantis Limited Ligand
US20060078533A1 (en) 2004-10-12 2006-04-13 Omoigui Osemwota S Method of prevention and treatment of aging and age-related disorders including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, arthritis, type 2 diabetes, dementia, alzheimer's disease and cancer
US20060275294A1 (en) 2002-08-22 2006-12-07 Omoigui Osemwota S Method of prevention and treatment of aging, age-related disorders and/or age-related manifestations including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, arthritis, type 2 diabetes, dementia, alzheimers disease and cancer
KR100442281B1 (ko) 2002-08-26 2004-08-02 엘지전자 주식회사 홈 네트워크 시스템의 제어 방법
CA2496523A1 (en) 2002-08-30 2004-03-11 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Human antihuman interleukin-6 antibody and fragment of the antibody
EP1572103A4 (en) 2002-11-15 2008-02-13 Centocor Inc ANTI-ANGIOGENIC USES OF IL-6 ANTAGONISTS
PT1610820E (pt) 2003-04-04 2010-12-16 Novartis Ag Formulações de elevada concentração de anticorpos e proteínas
JP4960096B2 (ja) 2003-09-22 2012-06-27 ペントラコール ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｉｌ−６の生物学的効果を減じる化合物の使用
BRPI0506679A (pt) 2004-02-11 2007-05-15 Warner Lambert Co métodos de tratar osteoartrite com antagonistas de il-6
WO2006072954A2 (en) 2005-01-05 2006-07-13 Compugen Ltd. Novel il-6 polynucleotides encoding variant il-6 polypeptides and methods using same
JO3058B1 (ar) 2005-04-29 2017-03-15 Applied Molecular Evolution Inc الاجسام المضادة لمضادات -اي ال-6,تركيباتها طرقها واستعمالاتها
CN101213214B (zh) 2005-05-20 2014-06-25 埃博灵克斯股份有限公司 针对冯威勒布兰特因子的单一结构域vhh抗体
US8163881B2 (en) 2005-05-31 2012-04-24 The Board Of Regents Of The University Of Texas System Immunoglobulin molecules with improved characteristics
AR057582A1 (es) 2005-11-15 2007-12-05 Nat Hospital Organization Agentes para suprimir la induccion de linfocitos t citotoxicos
EP1967209B1 (en) 2005-11-25 2012-06-06 Keio University Therapeutic agent for prostate cancer
BRPI0619595B8 (pt) 2005-12-09 2022-12-13 Ucb Pharma Sa anticorpo neutralizante, sequência de dna isolada, vetor de clonagem ou expressão, célula hospedeira, processo para a produção de um anticorpo, composição farmacêutica, e, uso de um anticorpo neutralizante humanizado
EP1977763A4 (en) 2005-12-28 2010-06-02 Chugai Pharmaceutical Co Ltd STABILIZER PREPARATION CONTAINING ANTIBODIES
ATE550353T1 (de) 2005-12-30 2012-04-15 Merck Patent Gmbh Die bindung von mit il-6ralpha komplexiertem il-6 an gp130 verhindernde anti-il-6-antikörper
US20110059101A9 (en) 2006-03-13 2011-03-10 Ablynx N.V. Amino Acid Sequences Directed Against Il-6 And Polypetides Comprising The Same For The Treatment Of Diseases And Disorders Associated With Il-6 Mediated Signalling
US7504106B2 (en) 2006-03-14 2009-03-17 Boris Skurkovich Method and composition for treatment of renal failure with antibodies and their equivalents as partial or complete replacement for dialysis
MX2009001110A (es) 2006-08-03 2009-05-11 Vaccinex Inc Anticuerpos monoclonales anti-il-6 y usos de los mismos.
EP2081960B1 (en) 2006-10-27 2018-06-27 Ablynx N.V. Intranasal delivery of polypeptides and proteins
TW200831528A (en) * 2006-11-30 2008-08-01 Astrazeneca Ab Compounds
AU2007327096A1 (en) 2006-11-30 2008-06-05 Astrazeneca Ab Antibodies specific for the complex of Interleukin-6 and the Interleukin-6 receptor
JP4966647B2 (ja) 2006-12-27 2012-07-04 矢崎総業株式会社 電気接続箱のシール構造
JP5419709B2 (ja) 2007-01-09 2014-02-19 ワイス・エルエルシー 抗ｉｌ−１３抗体製剤およびその使用
US20080279851A1 (en) 2007-05-07 2008-11-13 Medlmmune, Llc Anti-icos antibodies and their use in treatment of oncology, transplantation and autoimmune disease
US20090238825A1 (en) 2007-05-21 2009-09-24 Kovacevich Brian R Novel rabbit antibody humanization methods and humanized rabbit antibodies
US8062864B2 (en) 2007-05-21 2011-11-22 Alderbio Holdings Llc Nucleic acids encoding antibodies to IL-6, and recombinant production of anti-IL-6 antibodies
US8404235B2 (en) 2007-05-21 2013-03-26 Alderbio Holdings Llc Antagonists of IL-6 to raise albumin and/or lower CRP
US7906117B2 (en) 2007-05-21 2011-03-15 Alderbio Holdings Llc Antagonists of IL-6 to prevent or treat cachexia, weakness, fatigue, and/or fever
WO2008144757A1 (en) 2007-05-21 2008-11-27 Alder Biopharmaceuticals, Inc. Novel rabbit antibody humanization methods and humanized rabbit antibodies
LT2164514T (lt) 2007-05-21 2017-03-10 Alderbio Holdings Llc Il-6 antikūnai ir jų naudojimas
EP2170393A4 (en) 2007-06-19 2013-01-23 Univ Johns Hopkins ANTITROMOMBOTIC AGENTS AND METHOD OF USE THEREOF
AU2008268362A1 (en) 2007-06-26 2008-12-31 Medimmune, Llc Methods of treating RSV infections and related conditions
US9884899B2 (en) 2007-07-06 2018-02-06 Promedior, Inc. Methods for treating fibrosis using CRP antagonists
US8529897B2 (en) 2007-08-16 2013-09-10 Carnegie Mellon University Inflammation-regulating compositions and methods
US20100203009A1 (en) 2007-10-02 2010-08-12 The Uab Research Foundation Pathway for Th-17 Cell Development and Methods Utilizing Same
PE20091174A1 (es) 2007-12-27 2009-08-03 Chugai Pharmaceutical Co Ltd Formulacion liquida con contenido de alta concentracion de anticuerpo
MX2010012031A (es) 2008-05-13 2011-01-20 Novimmune Sa Anticuerpos anti-il-6/il-6r y metodos de uso de los mismos.
US8277804B2 (en) 2008-05-21 2012-10-02 Alderbio Holdings Llc Antagonists of IL-6 to prevent or treat thrombosis
US8188235B2 (en) * 2008-06-18 2012-05-29 Pfizer Inc. Antibodies to IL-6 and their uses
TWI440469B (zh) 2008-09-26 2014-06-11 Chugai Pharmaceutical Co Ltd Improved antibody molecules
US8337847B2 (en) 2008-11-25 2012-12-25 Alderbio Holdings Llc Methods of treating anemia using anti-IL-6 antibodies
WO2010065079A2 (en) 2008-11-25 2010-06-10 Alder Biopharmaceuticals, Inc. Antibodies to il-6 and use thereof
US9452227B2 (en) 2008-11-25 2016-09-27 Alderbio Holdings Llc Methods of treating or diagnosing conditions associated with elevated IL-6 using anti-IL-6 antibodies or fragments
US8323649B2 (en) 2008-11-25 2012-12-04 Alderbio Holdings Llc Antibodies to IL-6 and use thereof
WO2010088444A1 (en) 2009-01-29 2010-08-05 Medimmune, Llc Human anti-il-6 antibodies with extended in vivo half-life and their use in treatment of oncology, autoimmune diseases and inflammatory diseases
WO2011066369A2 (en) * 2009-11-24 2011-06-03 Alder Biopharmaceuticals, Inc. Antagonists of il-6 to raise albumin and/or lower crp
JO3417B1 (ar) 2010-01-08 2019-10-20 Regeneron Pharma الصيغ المستقرة التي تحتوي على الأجسام المضادة لمضاد مستقبل( interleukin-6 (il-6r
US20130224109A1 (en) 2010-07-20 2013-08-29 Beth Israel Deaconess Medical Center, Inc. Compositions and methods featuring il-6 and il-21 antagonists
SG189220A1 (en) 2010-10-06 2013-05-31 Regeneron Pharma Stabilized formulations containing anti-interleukin-4 receptor (il-4r) antibodies
WO2012064627A2 (en) * 2010-11-08 2012-05-18 Genentech, Inc. Subcutaneously administered anti-il-6 receptor antibody
US20120189621A1 (en) 2011-01-21 2012-07-26 Yann Dean Combination Therapies and Methods Using Anti-CD3 Modulating Agents and Anti-IL-6 Antagonists
US8753634B2 (en) 2011-03-03 2014-06-17 Apexigen, Inc. Anti-IL-6 receptor antibodies and methods of use
WO2013175276A1 (en) 2012-05-23 2013-11-28 Argen-X B.V Il-6 binding molecules
US20150246092A1 (en) 2012-10-22 2015-09-03 Stealth Peptides International, Inc. Methods for reducing risks associated with heart failure and factors associated therewith
BR112015008186A2 (pt) 2012-10-25 2017-09-19 Medimmune Llc formulação de um anticorpo estável e de baixa viscosidade
CN104903349B (zh) 2012-11-08 2018-10-19 十一生物治疗股份有限公司 Il-6拮抗剂及其应用
SG11201503637SA (en) 2012-11-08 2015-06-29 Clearside Biomedical Inc Methods and devices for the treatment of ocular diseases in human subjects
EP2968503B1 (en) 2013-03-15 2018-08-15 Intrinsic LifeSciences LLC Anti-hepcidin antibodies and uses thereof
US10745475B2 (en) * 2013-08-30 2020-08-18 Takeda Gmbh Antibodies neutralizing GM-CSF for use in the treatment of rheumatoid arthritis or as analgesics
US20160130340A1 (en) 2013-10-07 2016-05-12 Alderbio Holdings Llc Dosing regimens using anti-il-6 antibodies for the treatment of rheumatoid and psoriatic arthritis
US9017678B1 (en) 2014-07-15 2015-04-28 Kymab Limited Method of treating rheumatoid arthritis using antibody to IL6R
US8945560B1 (en) 2014-07-15 2015-02-03 Kymab Limited Method of treating rheumatoid arthritis using antibody to IL6R
US9139648B1 (en) 2014-07-15 2015-09-22 Kymab Limited Precision medicine by targeting human NAV1.9 variants for treatment of pain
UY36449A (es) 2014-12-19 2016-07-29 Novartis Ag Composiciones y métodos para anticuerpos dirigidos a bmp6
BR112018001853A2 (pt) 2015-07-31 2018-09-25 Astrazeneca Pharmaceuticals Lp métodos para tratamento de um distúrbio e para melhoria do tratamento de um distúrbio
KR20200012823A (ko) 2017-02-01 2020-02-05 예일 유니버시티 이뇨제 내성의 치료
EP3735421A4 (en) 2018-01-05 2021-09-22 Corvidia Therapeutics, Inc. METHOD OF TREATMENT OF IL-6 MEDIATED INFLAMMATION WITHOUT IMMUNSUPPRESSION

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11203636B2 (en) 2017-02-01 2021-12-21 Yale University Treatment of existing left ventricular heart failure
US11384143B2 (en) 2018-01-05 2022-07-12 Novo Nordisk A/S Methods for treating IL-6 mediated inflammation without immunosuppression
CN114206442A (zh) * 2019-01-31 2022-03-18 赛诺菲生物技术公司 用于治疗幼年特发性关节炎的抗il-6受体抗体
WO2020223565A1 (en) 2019-05-01 2020-11-05 Corvidia Therapeutics, Inc. Anti-il-6 antibody formulation

Also Published As

Publication number Publication date
US20230090473A1 (en) 2023-03-23
CO2020009510A2 (es) 2020-10-30
JP2021509668A (ja) 2021-04-01
US20220227856A1 (en) 2022-07-21
CN111787950A (zh) 2020-10-16
JP2023168447A (ja) 2023-11-24
MA51584A (fr) 2020-11-11
CA3087699A1 (en) 2019-07-11
PH12020551040A1 (en) 2021-08-23
ZA202004074B (en) 2022-03-30
EP3735421A1 (en) 2020-11-11
CL2023001681A1 (es) 2023-12-15
CL2020001790A1 (es) 2021-03-19
JP7395479B2 (ja) 2023-12-11
EA202091640A1 (ru) 2020-10-26
KR20230047223A (ko) 2023-04-06
BR112020013519A2 (pt) 2020-12-01
US20190248886A1 (en) 2019-08-15
US11384143B2 (en) 2022-07-12
SG11202006157VA (en) 2020-07-29
PE20211196A1 (es) 2021-07-01
KR20200116089A (ko) 2020-10-08
IL275696A (he) 2020-08-31
AU2019205936A1 (en) 2020-07-23
EP3735421A4 (en) 2021-09-22
RU2020125805A (ru) 2022-02-07
MX2020006882A (es) 2020-09-07
WO2019136312A1 (en) 2019-07-11
AU2019205936B2 (en) 2022-09-15

Similar Documents

Publication Publication Date Title
US11384143B2 (en) Methods for treating IL-6 mediated inflammation without immunosuppression
US20170210809A1 (en) Bispecific binding agents targeting the igf-1r and erbb3 pathways and uses thereof
JP2020516647A5 (he)
EP3685855B1 (en) Human anti-vegfr-2/kdr antibodies
JP2016527324A (ja) ベンラリツマブを使用して喘息の増悪率を低減する方法
AU2017201771A1 (en) Methods and compositions for treating lupus
US20180371082A1 (en) Novel antibody useful in neurological or neurodegenerative disorders
US20230287105A1 (en) Methods for treating cardiovascular disease
WO2023240031A1 (en) Compositions and methods for treating postural tachycardia syndrome
JP2019503987A (ja) 改良されたｐ２ｘ７受容体結合剤およびこれを含むポリペプチド
EA045389B1 (ru) Способ лечения сердечно-сосудистого заболевания
TW202305006A (zh) 與ｃｄ４７及ｐｄ—ｌ１特異性結合的雙特異性抗體
JP2018518153A5 (he)
WO2024153182A1 (zh) 抗pvrig/抗tigit双特异性抗体在治疗恶性肿瘤中的用途
US20220348652A1 (en) Recombinant antibodies, pharmaceutical compositions comprising the same, and uses thereof
Haddley Vobarilizumab. Anti-interleukin-6 receptor subunit alpha (CD126; IL-6R), Treatment of rheumatoid arthritis, Treatment of systemic lupus erythematosus
WO2016057726A2 (en) Human anti-vegfr-2/kdr antibodies
TW202430575A (zh) 抗ｐｖｒｉｇ／抗ｔｉｇｉｔ雙特異性抗體在治療惡性腫瘤中的用途

Legal Events

Date Code Title Description
AS Assignment

Owner name: CORVIDIA THERAPEUTICS, INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DEVALARAJA, MADHAV H.;DAVIDSON, MICHAEL H.;KAKKAR, RAHUL;SIGNING DATES FROM 20190311 TO 20190312;REEL/FRAME:048876/0359

STCB Information on status: application discontinuation

Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION

AS Assignment

Owner name: NOVO NORDISK A/S, DENMARK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CORVIDIA THERAPEUTICS, INC.;REEL/FRAME:054965/0550

Effective date: 20201029