How to treat IL-6-mediated inflammation without immunosuppression

Abstract

The problem that this invention aims to solve is to provide a novel method for treating IL-6-mediated inflammation that does not cause immunosuppression. [Solution] The present invention relates to a composition comprising an anti-IL-6 antibody for treating IL-6-mediated inflammation in a patient.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 62 / 614,134, filed on January 5, 2018, the entirety of which is incorporated herein by reference.

[0002] Sequence List This application includes a sequence listing submitted via EFS-Web, which is incorporated herein by reference in its entirety. The ASCII copy of the above, created in ______________, is named 38802US_sequencelisting.txt and has a size of ___________ bytes. [Background technology]

[0003] background Chronic inflammation is a characteristic feature of many diseases, including both classic rheumatic disorders and inflammatory bowel diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and psoriatic arthritis, as well as other systemic diseases that are increasingly understood to be associated with chronic inflammation, such as cardiovascular disease, kidney disease, neuroinflammatory diseases, anemia, cancer, and aging.

[0004] The pro-inflammatory cytokine IL-6 often plays a significant 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 development. Tocilizumab (Actemra), an anti-IL-6 receptor antibody, is approved for the treatment of rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and iatrogenic cytokine release syndrome. Sarilumab (Kevzara), another anti-IL-6 receptor antibody, is approved for the treatment of adult patients with moderate to severely active rheumatoid arthritis.

[0005] Inhibition of IL-6 can be effective, but treatment of chronic inflammation with IL-6 inhibitors using current dosing regimens often results in immunosuppression. Immunosuppression can lead to increased susceptibility to pathogens such as bacteria, fungi, and viruses. The prescribing information for Actemra approved by the FDA warns of the risk of serious infections leading to hospitalization or death, including tuberculosis, bacterial, invasive fungal, viral, and other opportunistic infections, and the prescribing information for Kevzara warns of serious infections leading to hospitalization or death, including bacterial, viral, invasive fungal, and other opportunistic infections.

[0006] Therefore, there is a need for new methods of treating IL-6-mediated inflammation that do not cause immunosuppression. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0007] Abstract The inventors have demonstrated that IL-6 antagonists can be administered at a dose, schedule, and duration sufficient to reduce inflammation without causing immunosuppression.

[0008] Thus, in a first aspect, a method of treating IL-6-mediated inflammation in a patient is provided. The method includes administering an IL-6 antagonist to a patient having IL-6-mediated inflammation at a dose sufficient to reduce inflammation without causing immunosuppression.

[0009] In some embodiments, the patient has elevated pre-treatment C-reactive protein (CRP) levels. In some embodiments, the patient's pre-treatment CRP level is at least 2 mg / L. In some embodiments, the patient's pre-treatment CRP level is at least 4 mg / L. In some embodiments, the patient's pre-treatment CRP level is at least 6 mg / L. In some embodiments, the patient's pre-treatment CRP level is at least 10 mg / L.

[0010] In some embodiments, the patient has elevated pre-treatment serum IL-6 levels. In some embodiments, the patient's pre-treatment serum IL-6 level is at least 4 pg / mL. In some embodiments, the patient's pre-treatment serum IL-6 level is at least 4 pg / mL. In some embodiments, the patient's pre-treatment serum IL-6 level is at least 5 pg / mL. In some embodiments, the patient's pre-treatment serum IL-6 level is at least 10 pg / mL.

[0011] In some embodiments, the inflammation is measured by the level of C-reactive protein (CRP). In some embodiments, the post-treatment CRP level is 2 mg / L or less. In some embodiments, the post-treatment CRP level is 1 mg / L or less. In some embodiments, the CRP level is reduced by at least 50% compared to the pre-treatment level. In some embodiments, the CRP level is reduced by at least 70% compared to the pre-treatment level. In some embodiments, the CRP level is reduced by at least 80% compared to the pre-treatment level. In some embodiments, the CRP level is reduced by at least 90% compared to the pre-treatment level.

[0012] In some embodiments, the immunosuppression is measured by the absolute neutrophil count (ANC). In some embodiments, the post-treatment ANC is at least 500 cells / μL. In some embodiments, the post-treatment ANC is at least 1000 cells / μL. In some embodiments, the post-treatment ANC is at least 1500 cells / μL. In some embodiments, the post-treatment ANC is at least 2000 cells / μL. In some embodiments, the ANC decreases by 2000 cells / μL or less compared to the pre-treatment level. In some embodiments, the ANC decreases by 1500 cells / μL or less compared to the pre-treatment level. In some embodiments, the ANC decreases by 1000 cells / μL or less compared to the pre-treatment level. In some embodiments, the ANC decreases by 500 cells / μL or less compared to the pre-treatment level. In some embodiments, the ANC decreases by 50% or less compared to the pre-treatment level. In some embodiments, the ANC decreases by 40% or less compared to the pre-treatment level. In some embodiments, the ANC decreases by 30% or less compared to the pre-treatment level. In some embodiments, the ANC decreases by 20% or less compared to the pre-treatment level. In some embodiments, the ANC decreases by 10% or less compared to the pre-treatment level. In some embodiments, the ANC does not decrease compared to the pre-treatment level.

[0013] In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of 30% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of 20% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of 10% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 25% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 20% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 15% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 10% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 5% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist.

[0014] In some embodiments, the IL-6 antagonist is an anti-IL-6 antibody.

[0015] In some embodiments, the anti-IL-6 antibody is COR-001. In some embodiments, COR-001 is administered intravenously at a monthly dose equivalent to 2-40 mg. In some embodiments, COR-001 is administered intravenously at a monthly dose equivalent to approximately 2 mg. In some embodiments, COR-001 is administered intravenously at a monthly dose equivalent to approximately 4 mg. In some embodiments, COR-001 is administered intravenously at a monthly dose equivalent to approximately 6 mg. In some embodiments, COR-001 is administered intravenously at a monthly dose equivalent to approximately 10 mg. In some embodiments, COR-001 is administered intravenously at a monthly dose equivalent to approximately 20 mg. In some embodiments, COR-001 is administered intravenously at a monthly dose equivalent to approximately 40 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly dose equivalent to 3-70 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 3 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 7 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 10 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 17 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 35 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 70 mg.

[0016] In some embodiments, the anti-IL-6 antibody is siltuximab. In some embodiments, siltuximab is administered intravenously at a monthly dose equivalent to 50-500 mg. In some embodiments, siltuximab is administered intravenously at a monthly dose equivalent to approximately 50 mg. In some embodiments, siltuximab is administered intravenously at a monthly dose equivalent to approximately 100 mg. In some embodiments, siltuximab is administered intravenously at a monthly dose equivalent to approximately 150 mg. In some embodiments, siltuximab is administered intravenously at a monthly dose equivalent to approximately 200 mg. In some embodiments, siltuximab is administered intravenously at a monthly dose equivalent to approximately 300 mg. In some embodiments, siltuximab is administered intravenously at a monthly dose equivalent to approximately 500 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly dose equivalent to 80-800 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 80 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 160 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 240 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 320 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 480 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 800 mg.

[0017] In some embodiments, the anti-IL-6 antibody is gerimumuzumab. In some embodiments, gerimumuzumab is administered intravenously at a monthly dose of 0.075 to 1.8 mg. In some embodiments, gerimumuzumab is administered intravenously at a monthly dose of approximately 0.075 mg. In some embodiments, gerimumuzumab is administered intravenously at a monthly dose of approximately 0.12 mg. In some embodiments, gerimumuzumab is administered intravenously at a monthly dose of approximately 0.3 mg. In some embodiments, gerimumuzumab is administered intravenously at a monthly dose of approximately 0.6 mg. In some embodiments, gerimumuzumab is administered intravenously at a monthly dose of approximately 0.9 mg. In some embodiments, gerimumuzumab is administered intravenously at a monthly dose of approximately 1.8 mg. In some embodiments, gerimumuzumab is administered subcutaneously at a monthly dose of 0.125 to 3 mg. In some embodiments, gerilimuzumab is administered subcutaneously at a monthly dose of approximately 0.125 mg. In some embodiments, gerilimuzumab is administered subcutaneously at a monthly dose of approximately 0.2 mg. In some embodiments, gerilimuzumab is administered subcutaneously at a monthly dose of approximately 0.5 mg. In some embodiments, gerilimuzumab is administered subcutaneously at a monthly dose of approximately 1 mg. In some embodiments, gerilimuzumab is administered subcutaneously at a monthly dose of approximately 1.5 mg. In some embodiments, gerilimuzumab is administered subcutaneously at a monthly dose of approximately 3 mg.

[0018] In some embodiments, the anti-IL-6 antibody is sirukmab. In some embodiments, sirukmab is administered intravenously at a monthly dose of 1.5 to 60 mg. In some embodiments, sirukmab is administered intravenously at a monthly dose of approximately 1.5 mg. In some embodiments, sirukmab is administered intravenously at a monthly dose of approximately 3 mg. In some embodiments, sirukmab is administered intravenously at a monthly dose of approximately 6 mg. In some embodiments, sirukmab is administered intravenously at a monthly dose of approximately 12 mg. In some embodiments, sirukmab is administered intravenously at a monthly dose of approximately 36 mg. In some embodiments, sirukmab is administered intravenously at a monthly dose of approximately 60 mg. In some embodiments, sirukmab is administered subcutaneously at a monthly dose of 2.5 to 100 mg. In some embodiments, sirukmab is administered subcutaneously at a monthly dose of approximately 2.5 mg. In some embodiments, sirukmab is administered subcutaneously at a monthly dose of approximately 5 mg. In some embodiments, sirukmab is administered subcutaneously at a monthly dose of approximately 10 mg. In some embodiments, sirukmab is administered subcutaneously at a monthly dose of approximately 20 mg. In some embodiments, sirukmab is administered subcutaneously at a monthly dose of approximately 60 mg. In some embodiments, sirukmab is administered subcutaneously at a monthly dose of approximately 100 mg.

[0019] In some embodiments, the anti-IL-6 antibody is crazakizumab. In some embodiments, crazakizumab is administered intravenously at a monthly dose equivalent to 3-60 mg. In some embodiments, crazakizumab is administered intravenously at a monthly dose equivalent to approximately 3 mg. In some embodiments, crazakizumab is administered intravenously at a monthly dose equivalent to approximately 6 mg. In some embodiments, crazakizumab is administered intravenously at a monthly dose equivalent to approximately 12 mg. In some embodiments, crazakizumab is administered intravenously at a monthly dose equivalent to approximately 24 mg. In some embodiments, crazakizumab is administered intravenously at a monthly dose equivalent to approximately 36 mg. In some embodiments, crazakizumab is administered intravenously at a monthly dose equivalent to approximately 60 mg. In some embodiments, crazakizumab is administered subcutaneously at a monthly dose equivalent to 5-100 mg. In some embodiments, crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 5 mg. In some embodiments, crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 10 mg. In some embodiments, crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 20 mg. In some embodiments, crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 40 mg. In some embodiments, crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 60 mg. In some embodiments, crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg.

[0020] In some embodiments, the anti-IL-6 antibody is olokizumab. In some embodiments, olokizumab is administered intravenously at a monthly dose of 1.8 to 60 mg. In some embodiments, olokizumab is administered intravenously at a monthly dose of approximately 1.8 mg. In some embodiments, olokizumab is administered intravenously at a monthly dose of approximately 3.6 mg. In some embodiments, olokizumab is administered intravenously at a monthly dose of approximately 9 mg. In some embodiments, olokizumab is administered intravenously at a monthly dose of approximately 18 mg. In some embodiments, olokizumab is administered intravenously at a monthly dose of approximately 45 mg. In some embodiments, olokizumab is administered intravenously at a monthly dose of approximately 60 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly dose of 3 to 100 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 3 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 6 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 15 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 30 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 72 mg. In some embodiments, olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg.

[0021] In some embodiments, 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.

[0022] In some embodiments, 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.

[0023] In some embodiments, 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.

[0024] In some embodiments, the IL-6 antagonist is an anti-IL-6R antibody.

[0025] In some embodiments, the anti-IL-6R antibody is tocilizumab. In some embodiments, tocilizumab is administered intravenously at a monthly dose equivalent to 50-500 mg. In some embodiments, tocilizumab is administered intravenously at a monthly dose equivalent to approximately 50 mg. In some embodiments, tocilizumab is administered intravenously at a monthly dose equivalent to approximately 100 mg. In some embodiments, tocilizumab is administered intravenously at a monthly dose equivalent to approximately 150 mg. In some embodiments, tocilizumab is administered intravenously at a monthly dose equivalent to approximately 250 mg. In some embodiments, tocilizumab is administered intravenously at a monthly dose equivalent to approximately 350 mg. In some embodiments, tocilizumab is administered intravenously at a monthly dose equivalent to approximately 500 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly dose equivalent to 80-800 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 80 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 160 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 240 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 400 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 560 mg. In some embodiments, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 800 mg.

[0026] In some embodiments, the anti-IL-6R antibody is sarilumab. In some embodiments, sarilumab is administered intravenously at a monthly dose equivalent to 12-120 mg. In some embodiments, sarilumab is administered intravenously at a monthly dose equivalent to approximately 12 mg. In some embodiments, sarilumab is administered intravenously at a monthly dose equivalent to approximately 24 mg. In some embodiments, sarilumab is administered intravenously at a monthly dose equivalent to approximately 48 mg. In some embodiments, sarilumab is administered intravenously at a monthly dose equivalent to approximately 60 mg. In some embodiments, sarilumab is administered intravenously at a monthly dose equivalent to approximately 72 mg. In some embodiments, sarilumab is administered intravenously at a monthly dose equivalent to approximately 120 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly dose equivalent to 20-200 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 20 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 40 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 80 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 120 mg. In some embodiments, sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 200 mg.

[0027] In some embodiments, the anti-IL-6R antibody is bovalilizumab. In some embodiments, bovalilizumab is administered intravenously at a monthly dose equivalent to 4 to 120 mg. In some embodiments, bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 4 mg. In some embodiments, bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 6 mg. In some embodiments, bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 30 mg. In some embodiments, bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 60 mg. In some embodiments, bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 84 mg. In some embodiments, bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 120 mg. In some embodiments, bovalilizumab is administered subcutaneously at a monthly dose equivalent to 7 to 200 mg. In some embodiments, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 7 mg. In some embodiments, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 10 mg. In some embodiments, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 50 mg. In some embodiments, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg. In some embodiments, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 140 mg. In some embodiments, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 200 mg.

[0028] In some embodiments, the IL-6 antagonist is a JAK inhibitor. In some embodiments, the IL-6 antagonist is a STAT3 inhibitor.

[0029] In some embodiments, the patient has hepcidin-mediated disorders.

[0030] In some embodiments, the patient has kidney disease. In some embodiments, the patient has chronic kidney disease. In some embodiments, the patient has KDOQI stage 1-5 chronic kidney disease. In some embodiments, the patient has KDOQI stage 3-5 chronic kidney disease. In some embodiments, the patient is not undergoing dialysis. In some embodiments, the patient has KDOQI stage 5 chronic kidney disease. In some embodiments, the patient is undergoing dialysis. In some embodiments, the patient has cardiorenal syndrome (CRS). In some embodiments, the patient has CRS type 4.

[0031] In some embodiments, 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 moderate 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.

[0032] In some embodiments, the patient has anemia. In some embodiments, the patient has chronic anemia. In some embodiments, the patient has iron-refractory iron deficiency anemia (IRIDA).

[0033] In some embodiments, the patient has diabetes. In some embodiments, the patient has type II diabetes. In some embodiments, the patient has insulin-resistant diabetes.

[0034] In some embodiments, the patient has liver disease. In some embodiments, the patient has non-alcoholic steatohepatitis (NASH).

[0035] In some embodiments, the patient has osteoporosis.

[0036] In some embodiments, the patient has depression.

[0037] In some embodiments, the patient has asthma.

[0038] In some embodiments, the patient has a 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).

[0039] In some embodiments, the patient has age-related macular degeneration (AMD).

[0040] In some embodiments, the patient has cancer.

[0041] In some embodiments, the cancer is selected from the group consisting of solid tumors, small cell lung cancer, non-small cell lung cancer, hematological malignancies, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), lymphoma, Hodgkin lymphoma, and hepatic adenoma.

[0042] In some embodiments, the patient has a skin disease.

[0043] In some embodiments, the method prevents aging in patients.

[0044] In another embodiment, a method for treating inflammation in patients with cardiovascular disease is provided herein. This method comprises administering an IL-6 antagonist to a patient with cardiovascular disease and a CRP level greater than 2 mg / L in a dose sufficient to reduce the CRP level to 2 mg / L or less without causing neutropenia.

[0045] In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is 30% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist.

[0046] In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is 20% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist.

[0047] In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is 10% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist.

[0048] In another embodiment, a method for treating inflammation in patients with chronic kidney disease (CKD) is provided herein. This method comprises administering an IL-6 antagonist to patients with CKD and CRP levels greater than 2 mg / L in a dose sufficient to reduce CRP levels to 2 mg / L or less without causing neutropenia.

[0049] In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is 30% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist.

[0050] In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is 20% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist.

[0051] In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is 10% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In certain embodiments, for example, the following are provided: (Item 1) A method for treating IL-6-mediated inflammation in a patient, A method comprising administering an IL-6 antagonist to a patient with IL-6-mediated inflammation in a dose sufficient to reduce inflammation without causing immunosuppression. (Item 2) The method according to item 1, wherein the patient has elevated pre-treatment C-reactive protein (CRP) levels. (Item 3) The method according to item 2, wherein the patient's pre-treatment CRP level is at least 2 mg / L. (Item 4) The method according to item 3, wherein the patient's pre-treatment CRP level is at least 4 mg / L. (Item 5) The method according to item 4, wherein the patient's pre-treatment CRP level is at least 6 mg / L. (Item 6) The method according to item 5, wherein the patient's pre-treatment CRP level is at least 10 mg / L. (Item 7) The method according to any of the above items, wherein the patient has elevated pre-treatment serum IL-6 levels. (Item 8) The method according to item 7, wherein the patient's pre-treatment serum IL-6 level is at least 2 pg / mL. (Item 9) The method according to item 8, wherein the patient's pre-treatment serum IL-6 level is at least 4 pg / mL. (Item 10) The method according to item 9, wherein the patient's pre-treatment serum IL-6 level is at least 5 pg / mL. (Item 11) The method according to item 10, wherein the patient's pre-treatment serum IL-6 level is at least 10 pg / mL. (Item 12) The method according to any of the above items, wherein the inflammation is measured by the level of C-reactive protein (CRP). (Item 13) The method described in item 12, wherein the post-treatment CRP level is 2 mg / L or less. (Item 14) The method described in item 13, wherein the post-treatment CRP level is 1 mg / L or less. (Item 15) The method according to item 12, wherein the CRP level is reduced by at least 50% compared to the pre-treatment level. (Item 16) The method according to item 15, wherein the CRP level is reduced by at least 70% compared to the pre-treatment level. (Item 17) The method according to item 16, wherein the CRP level is reduced by at least 80% compared to the pre-treatment level. (Item 18) The method according to item 17, wherein the CRP level is reduced by at least 90% compared to the pre-treatment level. (Item 19) The method according to any of the above items, wherein the immunosuppression is measured by absolute neutrophil count (ANC). (Item 20) The method according to item 19, wherein the ANC after the aforementioned treatment is at least 500 cells / μL. (Item 21) The method according to item 20, wherein the ANC after the aforementioned treatment is at least 1000 cells / μL. (Item 22) The method according to item 21, wherein the ANC after the treatment is at least 1500 cells / μL. (Item 23) The method according to item 21, wherein the ANC after the treatment is at least 2000 cells / μL. (Item 24) The method according to item 19, wherein the ANC decreases by 2000 cells / μL or less compared to the pre-treatment level. (Item 25) The method according to item 24, wherein the ANC decreases by 1500 cells / μL or less compared to the pre-treatment level. (Item 26) The method according to item 25, wherein the ANC decreases by 1000 cells / μL or less compared to the pre-treatment level. (Item 27) The method according to item 26, wherein the ANC decreases by 500 cells / μL or less compared to the pre-treatment level. (Item 28) The method according to item 19, wherein the ANC is reduced by 50% or less compared to the pre-treatment level. (Item 29) The method according to item 28, wherein the ANC is reduced by 40% or less compared to the pre-treatment level. (Item 30) The method according to item 29, wherein the ANC is reduced by 30% or less compared to the pre-treatment level. (Item 31) The method according to item 30, wherein the ANC is reduced by 20% or less compared to the pre-treatment level. (Item 32) The method according to item 31, wherein the ANC is reduced by 10% or less compared to the pre-treatment level. (Item 33) The method according to item 19, wherein the ANC does not decrease compared to the pre-treatment level. (Item 34) The method according to any of the above items, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 30% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 35) The method according to item 34, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 20% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 36) The method according to item 35, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 10% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 37) The method according to any one of items 1 to 33, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 25% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 38) The method according to any one of items 1 to 33, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 20% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 39) The method according to any one of items 1 to 33, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 15% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 40) The method according to any one of items 1 to 33, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 10% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 41) The method according to any one of items 1 to 33, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 5% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 42) The method according to any of the above items, wherein the IL-6 antagonist is an anti-IL-6 antibody. (Item 43) The method according to item 42, wherein the anti-IL-6 antibody is COR-001. (Item 44) The method described in item 43, wherein COR-001 is administered intravenously at a monthly dose equivalent to 2-40 mg. (Item 45) The method described in item 43, wherein COR-001 is administered intravenously at a monthly dose equivalent to approximately 2 mg. (Item 46) The method described in item 43, wherein COR-001 is administered intravenously at a monthly dose equivalent to approximately 4 mg. (Item 47) The method described in item 43, wherein COR-001 is administered intravenously at a monthly dose equivalent to approximately 6 mg. (Item 48) The method described in item 43, wherein COR-001 is administered intravenously at a monthly dose equivalent to approximately 10 mg. (Item 49) The method described in item 43, wherein COR-001 is administered intravenously at a monthly dose equivalent to approximately 20 mg. (Item 50) The method described in item 43, wherein COR-001 is administered intravenously at a monthly dose equivalent to approximately 40 mg. (Item 51) The method described in item 43, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to 3-70 mg. (Item 52) The method described in item 43, wherein COR-001 is administered subcutaneously at a monthly dose of approximately 3 mg. (Item 53) The method described in item 43, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 7 mg. (Item 54) The method described in item 43, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 10 mg. (Item 55) The method described in item 43, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 17 mg. (Item 56) The method described in item 43, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 35 mg. (Item 57) The method described in item 43, wherein COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 70 mg. (Item 58) The method according to item 42, wherein the anti-IL-6 antibody is siltuximab. (Item 59) The method described in item 58, in which siltuximab is administered intravenously at a monthly dose equivalent to 50-500 mg. (Item 60) The method described in item 58, wherein siltuximab is administered intravenously at a monthly dose equivalent to approximately 50 mg. (Item 61) The method described in item 58, wherein siltuximab is administered intravenously at a monthly dose equivalent to approximately 100 mg. (Item 62) The method described in item 58, in which siltuximab is administered intravenously at a monthly dose equivalent to approximately 150 mg. (Item 63) The method described in item 58, wherein siltuximab is administered intravenously at a monthly dose equivalent to approximately 200 mg. (Item 64) The method described in item 58, in which siltuximab is administered intravenously at a monthly dose equivalent to approximately 300 mg. (Item 65) The method described in item 58, wherein siltuximab is administered intravenously at a monthly dose equivalent to approximately 500 mg. (Item 66) The method described in item 58, in which siltuximab is administered subcutaneously at a monthly dose equivalent to 80-800 mg. (Item 67) The method described in item 58, in which siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 80 mg. (Item 68) The method described in item 58, wherein siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 160 mg. (Item 69) The method described in item 58, in which siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 240 mg. (Item 70) The method described in item 58, in which siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 320 mg. (Item 71) The method described in item 58, wherein siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 480 mg. (Item 72) The method described in item 58, in which siltuximab is administered subcutaneously at a monthly dose equivalent to approximately 800 mg. (Item 73) The method according to item 42, wherein the anti-IL-6 antibody is gerimimuzumab. (Item 74) The method described in item 73, in which gerilimuzumab is administered intravenously at a monthly dose equivalent to 0.075 to 1.8 mg. (Item 75) The method described in item 73, in which gerilimuzumab is administered intravenously at a monthly dose equivalent to approximately 0.075 mg. (Item 76) The method described in item 73, in which gerilimuzumab is administered intravenously at a monthly dose equivalent to approximately 0.12 mg. (Item 77) The method described in item 73, in which gerilimuzumab is administered intravenously at a monthly dose equivalent to approximately 0.3 mg. (Item 78) The method described in item 73, in which gerilimuzumab is administered intravenously at a monthly dose equivalent to approximately 0.6 mg. (Item 79) The method described in item 73, in which gerilimuzumab is administered intravenously at a monthly dose equivalent to approximately 0.9 mg. (Item 80) The method described in item 73, in which gerilimuzumab is administered intravenously at a monthly dose equivalent to approximately 1.8 mg. (Item 81) The method described in item 73, in which gerilimuzumab is administered subcutaneously at a monthly dose equivalent to 0.125 to 3 mg. (Item 82) The method described in item 73, in which gerilimuzumab is administered subcutaneously at a monthly dose equivalent to approximately 0.125 mg. (Item 83) The method described in item 73, in which gerilimuzumab is administered subcutaneously at a monthly dose equivalent to approximately 0.2 mg. (Item 84) The method described in item 73, in which gerilimuzumab is administered subcutaneously at a monthly dose of approximately 0.5 mg. (Item 85) The method described in item 73, wherein gerilimuzumab is administered subcutaneously at a monthly dose of approximately 1 mg. (Item 86) The method described in item 73, in which gerilimuzumab is administered subcutaneously at a monthly dose of approximately 1.5 mg. (Item 87) The method described in item 73, in which gerilimuzumab is administered subcutaneously at a monthly dose of approximately 3 mg. (Item 88) The method according to item 42, wherein the anti-IL-6 antibody is silkumab. (Item 89) The method described in item 88, wherein silkumab is administered intravenously at a monthly dose equivalent to 1.5 to 60 mg. (Item 90) The method described in item 88, wherein silkumab is administered intravenously at a monthly dose of approximately 1.5 mg. (Item 91) The method described in item 88, wherein silkumab is administered intravenously at a monthly dose of approximately 3 mg. (Item 92) The method described in item 88, wherein silkumab is administered intravenously at a monthly dose of approximately 6 mg. (Item 93) The method described in item 88, wherein silkumab is administered intravenously at a monthly dose of approximately 12 mg. (Item 94) The method described in item 88, wherein silkumab is administered intravenously at a monthly dose equivalent to approximately 36 mg. (Item 95) The method described in item 88, wherein silkumab is administered intravenously at a monthly dose equivalent to approximately 60 mg. (Item 96) The method described in item 88, wherein silkumab is administered subcutaneously at a monthly dose equivalent to 2.5 to 100 mg. (Item 97) The method described in item 88, wherein silkumab is administered subcutaneously at a monthly dose of approximately 2.5 mg. (Item 98) The method described in item 88, wherein silkumab is administered subcutaneously at a monthly dose of approximately 5 mg. (Item 99) The method described in item 88, wherein silkumab is administered subcutaneously at a monthly dose of approximately 10 mg. (Item 100) The method described in item 88, wherein silkumab is administered subcutaneously at a monthly dose of approximately 20 mg. (Item 101) The method described in item 88, wherein silkumab is administered subcutaneously at a monthly dose equivalent to approximately 60 mg. (Item 102) The method described in item 88, wherein silkumab is administered subcutaneously at a monthly dose of approximately 100 mg. (Item 103) The method according to item 42, wherein the anti-IL-6 antibody is crazakizumab. (Item 104) The method described in item 103, wherein crazakizumab is administered intravenously at a monthly dose equivalent to 3-60 mg. (Item 105) The method described in item 103, wherein crazakizumab is administered intravenously at a monthly dose of approximately 3 mg. (Item 106) The method described in item 103, wherein crazakizumab is administered intravenously at a monthly dose of approximately 6 mg. (Item 107) The method described in item 103, wherein crazakizumab is administered intravenously at a monthly dose equivalent to approximately 12 mg. (Item 108) The method described in item 103, in which crazakizumab is administered intravenously at a monthly dose equivalent to approximately 24 mg. (Item 109) The method described in item 103, wherein crazakizumab is administered intravenously at a monthly dose equivalent to approximately 36 mg. (Item 110) The method described in item 103, wherein crazakizumab is administered intravenously at a monthly dose equivalent to approximately 60 mg. (Item 111) The method described in item 103, wherein crazakizumab is administered subcutaneously at a monthly dose equivalent to 5-100 mg. (Item 112) The method described in item 103, wherein crazakizumab is administered subcutaneously at a monthly dose of approximately 5 mg. (Item 113) The method described in item 103, wherein crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 10 mg. (Item 114) The method described in item 103, wherein crazakizumab is administered subcutaneously at a monthly dose of approximately 20 mg. (Item 115) The method described in item 103, wherein crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 40 mg. (Item 116) The method described in item 103, wherein crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 60 mg. (Item 117) The method described in item 103, wherein crazakizumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg. (Item 118) The method according to item 42, wherein the anti-IL-6 antibody is olokizumab. (Item 119) The method described in item 118, wherein olokizumab is administered intravenously at a monthly dose equivalent to 1.8 to 60 mg. (Item 120) The method described in item 118, in which olokizumab is administered intravenously at a monthly dose equivalent to approximately 1.8 mg. (Item 121) The method described in item 118, in which olokizumab is administered intravenously at a monthly dose equivalent to approximately 3.6 mg. (Item 122) The method described in item 118, in which olokizumab is administered intravenously at a monthly dose equivalent to approximately 9 mg. (Item 123) The method described in item 118, in which olokizumab is administered intravenously at a monthly dose equivalent to approximately 18 mg. (Item 124) The method described in item 118, in which olokizumab is administered intravenously at a monthly dose equivalent to approximately 45 mg. (Item 125) The method described in item 118, in which olokizumab is administered intravenously at a monthly dose equivalent to approximately 60 mg. (Item 126) The method described in item 118, in which olokizumab is administered subcutaneously at a monthly dose equivalent to 3-100 mg. (Item 127) The method described in item 118, in which olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 3 mg. (Item 128) The method described in item 118, in which olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 6 mg. (Item 129) The method described in item 118, in which olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 15 mg. (Item 130) The method described in item 118, in which olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 30 mg. (Item 131) The method described in item 118, in which olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 72 mg. (Item 132) The method described in item 118, in which olokizumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg. (Item 133) The method according to item 42, wherein the anti-IL-6 antibody is VX30 (VOP-R003; Vaccinex). (Item 134) The method described in item 133, wherein VX30 (VOP-R003; Vaccinex) is administered intravenously. (Item 135) The method described in item 133, wherein VX30 (VOP-R003; Vaccinex) is administered subcutaneously. (Item 136) The method according to item 42, wherein the anti-IL-6 antibody is EB-007 (EBI-029; Eleven Bio). (Item 137) The method described in item 136, wherein EB-007 (EBI-029; Eleven Bio) is administered intravenously. (Item 138) The method described in item 136, wherein EB-007 (EBI-029; Eleven Bio) is administered subcutaneously. (Item 139) The method according to item 42, wherein the anti-IL-6 antibody is FM101 (Femta Pharmaceuticals, Lonza). (Item 140) The method described in item 139, wherein FM101 (Femta Pharmaceuticals, Lonza) is administered intravenously. (Item 141) The method described in item 139, wherein FM101 (Femta Pharmaceuticals, Lonza) is administered subcutaneously. (Item 142) The method according to any one of items 1 to 41, wherein the IL-6 antagonist is an anti-IL-6R antibody. (Item 143) The method according to item 142, wherein the anti-IL-6R antibody is tocilizumab. (Item 144) The method described in item 143, in which tocilizumab is administered intravenously at a monthly dose equivalent to 50-500 mg. (Item 145) The method described in item 143, wherein tocilizumab is administered intravenously at a monthly dose equivalent to approximately 50 mg. (Item 146) The method described in item 143, wherein tocilizumab is administered intravenously at a monthly dose equivalent to approximately 100 mg. (Item 147) The method described in item 143, wherein tocilizumab is administered intravenously at a monthly dose equivalent to approximately 150 mg. (Item 148) The method described in item 143, in which tocilizumab is administered intravenously at a monthly dose equivalent to approximately 250 mg. (Item 149) The method described in item 143, wherein tocilizumab is administered intravenously at a monthly dose equivalent to approximately 350 mg. (Item 150) The method described in item 143, wherein tocilizumab is administered intravenously at a monthly dose equivalent to approximately 500 mg. (Item 151) The method described in item 143, wherein tocilizumab is administered subcutaneously at a monthly dose equivalent to 80-800 mg. (Item 152) The method described in item 143, in which tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 80 mg. (Item 153) The method described in item 143, wherein tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 160 mg. (Item 154) The method described in item 143, wherein tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 240 mg. (Item 155) The method described in item 143, in which tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 400 mg. (Item 156) The method described in item 143, in which tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 560 mg. (Item 157) The method described in item 143, in which tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 800 mg. (Item 158) The method according to item 142, wherein the anti-IL-6R antibody is sarilumab. (Item 159) The method described in item 158, in which sarilumab is administered intravenously at a monthly dose equivalent to 12-120 mg. (Item 160) The method described in item 158, wherein sarilumab is administered intravenously at a monthly dose equivalent to approximately 12 mg. (Item 161) The method described in item 158, in which sarilumab is administered intravenously at a monthly dose equivalent to approximately 24 mg. (Item 162) The method described in item 158, in which sarilumab is administered intravenously at a monthly dose equivalent to approximately 48 mg. (Item 163) The method described in item 158, in which sarilumab is administered intravenously at a monthly dose equivalent to approximately 60 mg. (Item 164) The method described in item 158, in which sarilumab is administered intravenously at a monthly dose equivalent to approximately 72 mg. (Item 165) The method described in item 158, in which sarilumab is administered intravenously at a monthly dose equivalent to approximately 120 mg. (Item 166) The method described in item 158, in which sarilumab is administered subcutaneously at a monthly dose equivalent to 20-200 mg. (Item 167) The method described in item 158, in which sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 20 mg. (Item 168) The method described in item 158, in which sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 40 mg. (Item 169) The method described in item 158, in which sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 80 mg. (Item 170) The method described in item 158, in which sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg. (Item 171) The method described in item 158, in which sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 120 mg. (Item 172) The method described in item 158, in which sarilumab is administered subcutaneously at a monthly dose equivalent to approximately 200 mg. (Item 173) The method according to item 142, wherein the anti-IL-6R antibody is bovalilizumab. (Item 174) The method described in item 173, in which bovalilizumab is administered intravenously at a monthly dose equivalent to 4-120 mg. (Item 175) The method described in item 173, in which bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 4 mg. (Item 176) The method described in item 173, in which bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 6 mg. (Item 177) The method described in item 173, in which bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 30 mg. (Item 178) The method described in item 173, in which bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 60 mg. (Item 179) The method described in item 173, in which bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 84 mg. (Item 180) The method described in item 173, in which bovalilizumab is administered intravenously at a monthly dose equivalent to approximately 120 mg. (Item 181) The method described in item 173, in which bovalilizumab is administered subcutaneously at a monthly dose equivalent to 7-200 mg. (Item 182) The method described in item 173, in which bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 7 mg. (Item 183) The method described in item 173, in which bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 10 mg. (Item 184) The method described in item 173, in which bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 50 mg. (Item 185) The method described in item 173, in which bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg. (Item 186) The method described in item 173, in which bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 140 mg. (Item 187) The method described in item 173, in which bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 200 mg. (Item 188) The method according to any one of items 1 to 41, wherein the IL-6 antagonist is a JAK inhibitor. (Item 189) The method according to any one of items 1 to 41, wherein the IL-6 antagonist is a STAT3 inhibitor. (Item 190) The method described in any of the above items, wherein the patient has a hepcidin-mediated disorder. (Item 191) The method according to any one of items 1 to 189, wherein the patient has renal disease. (Item 192) The method described in item 191, wherein the patient has chronic kidney disease. (Item 193) The method described in item 192 for the aforementioned patient having KDOQI stage 1-5 chronic kidney disease. (Item 194) The method described in item 193 for the aforementioned patient having KDOQI stage 3-5 chronic kidney disease. (Item 195) The method described in item 194, for the patient who is not receiving dialysis. (Item 196) The method described in item 193, for the aforementioned patient having KDOQI stage 5 chronic kidney disease. (Item 197) The method described in item 196, wherein the patient is undergoing dialysis. (Item 198) The method described in item 192, wherein the patient has cardiorenal syndrome (CRS). (Item 199) The method described in item 198, wherein the patient has CRS type 4. (Item 200) The method according to any one of items 1 to 189, wherein the patient has cardiovascular disease. (Item 201) The method according to item 200, wherein the patient has diuretic-resistant heart failure. (Item 202) The method according to item 200, wherein the patient has congestive heart failure (CHF). (Item 203) The method according to item 202, wherein the patient has congestive heart failure (CHF) with reduced ejection fraction. (Item 204) The method according to item 202, wherein the patient has congestive heart failure (CHF) with a moderate ejection fraction. (Item 205) The method according to item 202, wherein the patient has congestive heart failure (CHF) with preserved ejection fraction. (Item 206) The method according to item 200, wherein the patient has acute coronary syndrome. (Item 207) The method according to item 200, wherein the patient has atherosclerosis. (Item 208) The method according to any one of items 1 to 189, wherein the patient has anemia. (Item 209) The method described in item 208, wherein the patient has chronic anemia. (Item 210) The method according to item 208, wherein the patient has iron-refractory iron deficiency anemia (IRIDA). (Item 211) The method according to any one of items 1 to 189, wherein the patient has diabetes. (Item 212) The method according to item 211, wherein the patient has type 2 diabetes. (Item 213) The method according to item 211, wherein the patient has insulin-resistant diabetes. (Item 214) The method according to any one of items 1 to 189, wherein the patient has liver disease. (Item 215) The method according to item 214, wherein the patient has non-alcoholic steatohepatitis (NASH). (Item 216) The method according to any one of items 1 to 189, wherein the patient has osteoporosis. (Item 217) The method according to any one of items 1 to 189, wherein the patient has depression. (Item 218) The method according to any one of items 1 to 189, wherein the patient has asthma. (Item 219) The method according to any one of items 1 to 189, wherein the patient has a neuroinflammatory disorder. (Item 220) The method according to item 219, wherein the patient has Alzheimer's disease. (Item 221) The method according to item 219, wherein the patient has Parkinson's disease. (Item 222) The method according to item 219, wherein the patient has multiple sclerosis. (Item 223) The method according to item 219, wherein the patient has amyotrophic lateral sclerosis (ALS). (Item 224) The method according to any one of items 1 to 189, wherein the patient has age-related macular degeneration (AMD). (Item 225) The method according to any one of items 1 to 189, wherein the patient has cancer. (Item 226) The method according to item 225, wherein the cancer is selected from the group consisting of solid tumors, small cell lung cancer, non-small cell lung cancer, hematological malignancies, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), lymphoma, Hodgkin lymphoma, and hepatic adenoma. (Item 227) The method according to any one of items 1 to 189, wherein the patient has a skin disease. (Item 228) The method described in any one of items 1 to 189, wherein the method prevents aging in the patient. (Item 229) A method for treating inflammation in patients with cardiovascular disease, A method comprising administering an IL-6 antagonist to patients with cardiovascular disease and CRP levels greater than 2 mg / L at a dose sufficient to reduce CRP levels to 2 mg / L or less without causing neutropenia. (Item 230) The method according to item 229, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 30% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 231) The method according to item 230, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 20% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 232) The method according to item 231, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 10% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 233) A method for treating inflammation in patients with chronic kidney disease (CKD), A method comprising administering an IL-6 antagonist to patients with CKD and CRP levels greater than 2 mg / L at a dose sufficient to reduce CRP levels to 2 mg / L or less without causing neutropenia. (Item 234) The method according to item 233, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 30% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 235) The method according to item 234, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 20% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. (Item 236) The method according to item 235, wherein the IL-6 antagonist is administered at a monthly equivalent dose that is 10% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist.

[0052] These and other features, embodiments, and advantages of the present invention will be better understood in connection with the following description and accompanying drawings. [Brief explanation of the drawing]

[0053] [Figure 1] Figure 1 shows a schematic diagram of the dose escalation in the Phase 1 / Phase 2 randomized, double-blind, placebo-controlled trial of COR-001 in hemodialysis patients as described in Example 1. [Figure 2] Figure 2 shows the treatment and safety follow-up schedules and efficacy analysis. [Figure 3]Figures 3A and 3B show the results of C-reactive protein (CRP) responder analysis after treatment with COR-001 (anti-IL-6) or canakinumab (anti-IL-1β). Figure 3A shows the percentage of C-reactive protein responders after intravenous treatment with COR-001 in patients with stage 5 chronic kidney disease undergoing dialysis in the clinical trial described in Example 1. Baseline hsCRP was 12.4 mg / L. Responders were defined as those with a 12-week mean hsCRP < 2 mg / L. Figure 3B shows the percentage of C-reactive protein responders after treatment with canakinumab in the CANTOS trial, as described in the research literature. Baseline hsCRP was 5.5 mg / L. Responders were defined as those with a 3-month mean hsCRP < 2 mg / L. [Figure 4] Figure 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 an increase of 1 g / dL or more at 29 days. Principal investigators were not permitted to change ESA dosage until after 29 days. [Figure 5] Figure 5 shows the effect of COR-001 on diastolic cardiac parameters, NT-proBNP. [Figure 6] Figures 6A and 6B show the percentage of adverse responders for neutrophils and platelets. Figure 6A shows the percentage of adverse neutrophil responders. Adverse responders were defined as those with a 12-week mean neutrophil count <2 × 10⁶ / mL. Figure 6B shows the percentage of adverse platelet responders. Adverse responders were defined as those with a 12-week mean platelet count <100 × 10⁶ / mL. [Modes for carrying out the invention]

[0054] Detailed explanation 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art.

[0055] As used herein, “interleukin-6 (IL-6)” or “IL-6 polypeptide” refers to a polypeptide or fragment thereof that has at least about 85% or more amino acid identity with the amino acid sequence provided in NCBI accession number NP_000591, and that possesses IL-6 biological activity. IL-6 is a pleotropic cytokine with multiple biological functions. Exemplary IL-6 biological activities include immunostimulatory and pro-inflammatory activity. An exemplary IL-6 amino acid sequence is provided below: [ka]

[0056] As used herein, “interleukin-6 (IL-6) nucleic acid” refers to a polynucleotide encoding the interleukin-6 (IL-6) polypeptide. An exemplary interleukin-6 (IL-6) nucleic acid sequence is provided under NCBI accession number NM_000600. The exemplary sequence under NCBI accession number NM_000600 is provided below: [ka] [ka]

[0057] As used herein, the term "interleukin-6 receptor (IL-6R) complex" refers to a protein complex comprising IL-6 receptor subunit α (IL-6Rα) and interleukin-6 signaling glycoprotein 130 (gp130), also known as interleukin-6 receptor subunit β (IL-6Rβ).

[0058] As used herein, “interleukin-6 receptor subunit α (IL-6Rα) polypeptide” refers to a polypeptide or fragment thereof that has at least about 85% or more amino acid identity with the amino acid sequence provided in NCBI accession number NP_000556 or NP_852004, and that possesses IL-6 receptor biological activity. Exemplary IL-6Rα biological activity includes binding to IL-6, binding to glycoprotein 130 (gp130), and regulation of cell proliferation and differentiation. An exemplary IL-6R sequence is provided below: [ka]

[0059] As used herein, “glycoprotein 130” (gp130) or “interleukin-6 receptor subunit β (IL-6Rβ) polypeptide” refers to a polypeptide or fragment thereof that has at least about 85% or more amino acid identity with the amino acid sequences provided in NCBI accession numbers NP_002175, NP_786943, or NP_001177910, and that possesses IL-6 receptor biological activity. Exemplary IL-6Rβ biological activities include binding to IL-6Rα, IL-6 receptor signaling activity, and regulation of cell proliferation, differentiation, and hepcidin expression. An exemplary IL-6Rβ sequence is provided below: [ka]

[0060] Unless otherwise specified, “IL-6 antagonist” refers to an agent capable of reducing the biological activity of IL-6. IL-6 antagonists include agents that reduce the level of IL-6 polypeptides in serum, including agents that reduce the expression of IL-6 polypeptides or nucleic acids; agents that reduce the ability of IL-6 to bind to IL-6R; agents that reduce the expression of IL-6R; and agents that reduce signaling by the IL-6R receptor when bound by IL-6. In preferred embodiments, IL-6 antagonists reduce IL-6 biological activity by at least about 10%, about 20%, about 30%, about 50%, about 70%, about 80%, about 90%, about 95%, or about 100%. As further described below, IL-6 antagonists include IL-6-binding polypeptides, e.g., anti-IL-6 antibodies and their antigen-binding fragments or derivatives thereof; IL-6R-binding polypeptides, e.g., anti-IL-6R antibodies and their antigen-binding fragments or derivatives thereof; and synthetic chemical molecules, e.g., JAK1 and JAK3 inhibitors.

[0061] The terms "IL-6 antibody" or "anti-IL-6 antibody" refer to antibodies that specifically bind to IL-6. Anti-IL-6 antibodies include monoclonal and polyclonal antibodies that are specific to IL-6, as well as their antigen-binding fragments or derivatives. IL-6 antibodies are described in more detail below.

[0062] As used herein, the terms “IL-6-mediated inflammation” or “IL-6-mediated inflammatory disorder” refer to inflammation or inflammation-related disorders in which IL-6 is known or suspected to contribute to the development or symptoms of inflammation.

[0063] The term "C-reactive protein" or "CRP" refers to a polypeptide or fragment thereof that has at least approximately 85% or more amino acid identity with the amino acid sequence provided in NCBI accession number NP_000558, and possesses complement-activating activity. CRP levels increase in response to inflammation and can be measured by the hsCRP (high-sensitivity C-reactive protein) test. An example CRP sequence is provided below: [ka]

[0064] As used herein, “hepcidin” refers to a polypeptide having at least about 85% or more amino acid identity with the amino acid sequence or a biologically active fragment thereof provided in NCBI accession number NP_066998 (“hepcidin preprotein”). Exemplary hepcidin biological activities include binding to and reducing the levels of ferroportin, an iron efflux channel; 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: [ka] Referring to the above sequence, hepcidin exists in various forms, including preprohormone (amino acids 25-84), prohormone (amino acids 25-84), and mature forms named hepcidin-25 (amino acids 60-84), hepcidin-22 (amino acids 63-84), and hepcidin-20 (amino acids 65-84).

[0065] "Hepcidin-mediated disorders" are any disorders in which hepcidin expression contributes to either the onset of the disorder or its symptoms.

[0066] The term "immune suppression" or "immunosuppression" refers to a decrease in the activation or efficacy of the immune system. Immunosuppression can be measured by the number of white blood cells, such as neutrophils.

[0067] As used herein, “neutrophil” of “neutrocyte” refers to a type of white blood cell that is an essential part of the innate immune system. Absolute neutrophil count (ANC) can be used in diagnosis and prognosis. A low neutrophil count is referred to as neutropenia.

[0068] The term "drug" refers to any compound or composition suitable for administration in therapeutic use, and explicitly includes chemical compounds; proteins containing antibodies or their antigen-binding fragments; peptides; and nucleic acid molecules.

[0069] The term "subject" refers to a human subject or a non-human mammal subject, including but not limited to cattle, horses, dogs, sheep, cats, mice, and rodents (including the genus *Rattus*). "Patient" refers to a human subject requiring treatment.

[0070] As used herein, terms such as “treat,” “treating,” and “treatment” refer to reducing or alleviating a disorder and / or associated signs or symptoms, or slowing or halting their progression. It will be understood that treating a disease or symptom does not require, but does not preclude, complete elimination of the disorder, associated symptoms, or symptoms.

[0071] As used herein, “pre-treatment” means prior to the first administration of an IL-6 antagonist according to the method described herein. Pre-treatment often includes, but does not exclude, prior administration of treatments other than IL-6 antagonists.

[0072] As used herein, “post-treatment” means after the administration of an IL-6 antagonist in accordance with the methods described herein. Post-treatment includes after any administration of an IL-6 antagonist at any dose described herein. Post-treatment also includes after the treatment stage of the IL-6 antagonist.

[0073] In this disclosure, “comprises,” “comprising,” “containing,” “having,” “includes,” “including,” and their linguistic variations have the meanings given to them in U.S. patent law and permit the presence of further components other than those expressly listed.

[0074] The term "biological sample" refers to any tissue, cell, fluid, or other material derived from a living organism (e.g., a human subject). In one embodiment, the biological sample is serum or blood.

[0075] Unless otherwise specified, the numbering of antibody constant region residues follows the EU index, as in Kabat.

[0076] 2. How to treat IL-6-mediated inflammation In a first embodiment, a method for treating IL-6-mediated inflammation in a patient is presented. The method comprises administering an IL-6 antagonist to a patient having IL-6-mediated inflammation in a dose sufficient to reduce inflammation without causing immunosuppression.

[0077] 2.1. Pre-treatment serum CRP and IL-6 levels In the method described herein, the patient has IL-6-mediated inflammation.

[0078] In a typical embodiment, the patient has elevated pre-treatment C-reactive protein (CRP) levels.

[0079] In some embodiments, the patient has a pre-treatment CRP level of at least 2 mg / L. In some embodiments, the patient has a pre-treatment CRP level of 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 a pre-treatment CRP level of 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 of at least 2 mg / L. In various embodiments, the patient has a pre-treatment CRP level of at least 2.5 mg / L. In various embodiments, the patient has a pre-treatment CRP level of at least 5 mg / L. In various embodiments, the patient has a pre-treatment CRP level of at least 7.5 mg / L. In various embodiments, the patient has a pre-treatment CRP level of at least 10 mg / L. In various embodiments, the patient has a pre-treatment CRP level of at least 12.5 mg / L. In various embodiments, the patient has a pre-treatment CRP level of at least 15 mg / L.

[0080] In some embodiments of the methods described herein, the patient has elevated pre-treatment serum IL-6 levels.

[0081] In some embodiments, 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. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 2 pg / mL. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 2.5 pg / mL. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 4 pg / mL. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 5 pg / mL. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 7.5 pg / mL. In another embodiment, the patient has a pre-treatment serum IL-6 level of at least 10 pg / mL. In yet another embodiment, the patient has a pre-treatment serum IL-6 level of at least 12.5 pg / mL. In yet another embodiment, the patient has a pre-treatment serum IL-6 level of at least 15 pg / mL.

[0082] In some embodiments, the patient has elevated pre-treatment serum CRP levels and elevated pre-treatment IL-6 levels. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 2 pg / mL and a pre-treatment CRP level of at least 2 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 2 pg / mL and a pre-treatment CRP level of at least 2.5 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 2 pg / mL and a pre-treatment CRP level of at least 5 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 2 pg / mL and a pre-treatment CRP level of at least 10 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 4 pg / mL and a pre-treatment CRP level of at least 2 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 4 pg / mL and a pre-treatment CRP level of at least 2.5 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 4 pg / mL and a pre-treatment CRP level of at least 5 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 4 pg / mL and a pre-treatment CRP level of at least 10 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 5 pg / mL and a pre-treatment CRP level of at least 2 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 5 pg / mL and a pre-treatment CRP level of at least 2.5 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 5 pg / mL and a pre-treatment CRP level of at least 5 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 5 pg / mL and a pre-treatment CRP level of at least 10 mg / L. In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 10 pg / mL and a pre-treatment CRP level of at least 2 mg / L.In one embodiment, the patient has a pre-treatment serum IL-6 level of at least 10 pg / mL and a pre-treatment CRP level of at least 2.5 mg / L. In another embodiment, the patient has a pre-treatment serum IL-6 level of at least 10 pg / mL and a pre-treatment CRP level of at least 5 mg / L. In yet another embodiment, the patient has a pre-treatment serum IL-6 level of at least 10 pg / mL and a pre-treatment CRP level of at least 10 mg / L.

[0083] 2.2. Decrease in IL-6 and C-reactive protein (CRP) In a typical embodiment, an IL-6 antagonist is administered in a dose sufficient to lower the patient's free serum IL-6 level below pre-treatment levels.

[0084] In some embodiments, free serum IL-6 levels decrease by at least 10% compared to pre-treatment levels. In various embodiments, free serum IL-6 levels decrease by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to pre-treatment levels. In one embodiment, free serum IL-6 levels decrease by at least 20% compared to pre-treatment levels. In one embodiment, free serum IL-6 levels decrease by at least 30% compared to pre-treatment levels. In one embodiment, free serum IL-6 levels decrease by at least 40% compared to pre-treatment levels. In one embodiment, free serum IL-6 levels decrease by at least 50% compared to pre-treatment levels. In one embodiment, free serum IL-6 levels decrease by at least 60% compared to pre-treatment levels. In one embodiment, free serum IL-6 levels decrease by at least 70% compared to pre-treatment levels. In one embodiment, free serum IL-6 levels decrease by at least 80% compared to pre-treatment levels. In one embodiment, free serum IL-6 levels are reduced by at least 90% compared to pre-treatment levels.

[0085] In some embodiments, the IL-6 antagonist is administered in a dose sufficient to lower the patient's CRP level below pre-treatment levels. In some embodiments, IL-6-mediated inflammation is measured by CRP levels.

[0086] In one embodiment, the post-treatment CRP level is 5 mg / L or less. In another embodiment, the post-treatment CRP level is 2.5 mg / L or less. In yet another embodiment, the post-treatment CRP level is 2 mg / L or less. In yet another embodiment, the post-treatment CRP level is 1 mg / L or less.

[0087] In some embodiments, CRP levels decrease by at least 10% compared to pre-treatment levels. In various embodiments, CRP levels decrease by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to pre-treatment levels. In one embodiment, CRP levels decrease by at least 20% compared to pre-treatment levels. In one embodiment, CRP levels decrease by at least 30% compared to pre-treatment levels. In one embodiment, CRP levels decrease by at least 40% compared to pre-treatment levels. In one embodiment, CRP levels decrease by at least 50% compared to pre-treatment levels. In one embodiment, CRP levels decrease by at least 60% compared to pre-treatment levels. In one embodiment, CRP levels decrease by at least 70% compared to pre-treatment levels. In one embodiment, CRP levels decrease by at least 80% compared to pre-treatment levels. In one embodiment, CRP levels decrease by at least 90% compared to pre-treatment levels.

[0088] 2.3. Neutrophil levels 2.3.1. Absolute Neutrophil Count (ANC) In the methods described herein, the IL-6 antagonist is administered in a dose sufficient to reduce inflammation without causing immunosuppression.

[0089] In some embodiments, patient immunosuppression is measured by absolute neutrophil count (ANC).

[0090] In some embodiments, the post-treatment ANC is at least 300 cells / μL. In various embodiments, the post-treatment ANC is at least 500 cells / μL, 600 cells / μL, 700 cells / μL, 800 cells / μL, 900 cells / μL, 1000 cells / μL, 1100 cells / μL, 1200 cells / μL, 1300 cells / μL, 1400 cells / μL, 1500 cells / μL, 1600 cells / μL, 1700 cells / μL, 1800 cells / μL, 1900 cells / μL, or 2000 cells / μL. In one embodiment, the post-treatment ANC is at least 500 cells / μL. In one embodiment, the post-treatment ANC is at least 750 cells / μL. In one embodiment, the post-treatment ANC is at least 1000 cells / μL. In one embodiment, the post-treatment ANC is at least 1250 cells / μL. In one embodiment, the post-treatment ANC is at least 1500 cells / μL. In another embodiment, the post-treatment ANC is at least 1750 cells / μL. In yet another embodiment, the post-treatment ANC is at least 2000 cells / μL.

[0091] In some embodiments, the ANC decreases by 2500 cells / μL or less compared to the pre-treatment level. In various embodiments, the ANC decreases by 2000 cells / μL, 1900 cells / μL, 1800 cells / μL, 1700 cells / μL, 1600 cells / μL, 1500 cells / μL, 1400 cells / μL, 1300 cells / μL, 1200 cells / μL, 1100 cells / μL, 1000 cells / μL, 900 cells / μL, 800 cells / μL, 700 cells / μL, 600 cells / μL, or 500 cells / μL or less compared to the pre-treatment level. In one embodiment, the ANC decreases by 2000 cells / μL or less compared to the pre-treatment level. In one embodiment, the ANC decreases by 1750 cells / μL or less compared to the pre-treatment level. In one embodiment, the ANC decreases by 1500 cells / μL or less compared to the pre-treatment level. In one embodiment, the ANC decreases by 1250 cells / μL or less compared to the pre-treatment level. In another embodiment, the ANC decreases by 1000 cells / μL or less compared to the pre-treatment level. In yet another embodiment, the ANC decreases by 750 cells / μL or less compared to the pre-treatment level. In yet another embodiment, the ANC decreases by 500 cells / μL or less compared to the pre-treatment level.

[0092] In some embodiments, ANC decreases by 70% or less compared to the pre-treatment level. In various embodiments, ANC decreases by 60%, 50%, 40%, 30%, 20%, 10%, or 5% or less compared to the pre-treatment level. In one embodiment, ANC decreases by 60% or less compared to the pre-treatment level. In one embodiment, ANC decreases by 50% or less compared to the pre-treatment level. In one embodiment, ANC decreases by 40% or less compared to the pre-treatment level. In one embodiment, ANC decreases by 30% or less compared to the pre-treatment level. In one embodiment, ANC decreases by 20% or less compared to the pre-treatment level. In one embodiment, ANC decreases by 10% or less compared to the pre-treatment level. In one embodiment, ANC decreases by 5% or less compared to the pre-treatment level.

[0093] In some embodiments, the ANC does not decrease compared to the pre-treatment level.

[0094] 2.4. Lipoprotein(a) Level In some embodiments, the IL-6 antagonist is administered at a dosage sufficient to lower the patient's lipoprotein(a) level below the pre-treatment level.

[0095] In some embodiments, the lipoprotein(a) level decreases by at least 10% compared to the pre-treatment level. In various embodiments, the lipoprotein(a) level decreases by at least 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to the pre-treatment level. In certain embodiments, the lipoprotein(a) level decreases by at least 20% compared to the pre-treatment level. In certain embodiments, the lipoprotein(a) level decreases by at least 30% compared to the pre-treatment level. In certain embodiments, the lipoprotein(a) level decreases by at least 40% compared to the pre-treatment level. In certain embodiments, the lipoprotein(a) level decreases by at least 50% compared to the pre-treatment level. In certain embodiments, the lipoprotein(a) level decreases by at least 60% compared to the pre-treatment level. In certain embodiments, the lipoprotein(a) level decreases by at least 70% compared to the pre-treatment level. In certain embodiments, the lipoprotein(a) level decreases by at least 80% compared to the pre-treatment level. In certain embodiments, the lipoprotein(a) level decreases by at least 90% compared to the pre-treatment level.

[0096] 2.5. LDL Level In some embodiments, the IL-6 antagonist is administered at a dosage sufficient to lower the patient's lipoprotein(a) level without significantly increasing the patient's low density lipoprotein (LDL) level.

[0097] In some embodiments, the LDL level increases by 15% or less compared to the pre-treatment level. In various embodiments, the LDL level increases by 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2% or 1% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 12% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 10% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 8% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 6% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 5% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 4% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 3% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 2% or less compared to the pre-treatment level. In certain embodiments, the LDL level increases by 1% or less compared to the pre-treatment level.

[0098] In certain embodiments, the LDL level does not increase compared to the pre-treatment level.

[0099] 2.6. IL-6-mediated Inflammatory Disorders In the methods described herein, the patient has an IL-6-mediated inflammatory disorder.

[0100] 2.6.1 Non-Hepcidin-Mediated Inflammatory Disorders In various embodiments, the IL-6-mediated inflammatory disorder is not a hepcidin-mediated disorder. Hepcidin-mediated disorders are described in U.S. Patent Publication No. 2017 / 0029499, the entire disclosure of which is incorporated herein by reference.

[0101] 2.6.2 Hepcidin-Mediated Inflammatory Disorders In various embodiments, IL-6-mediated inflammatory disorders are hepcidin-mediated disorders. Hepcidin-mediated disorders are described in U.S. Patent Publication 2017 / 0029499, the entire disclosure of which is incorporated herein by reference. In certain embodiments, a patient has hepcidin-mediated disorders and at least one copy of the major allele (amino acid 736A) at TMPRSS6rs855791SNP. In other embodiments, a patient has hepcidin-mediated disorders and is homozygous with respect to the non-major allele (amino acid 736V) at TMPRSS6rs855791SNP. In some embodiments, a patient has hepcidin-mediated disorders and the genotype at TMPRSS6rs855791SNP is unknown.

[0102] 2.6.3 Non-autoimmune inflammatory disorders In various embodiments, IL-6-mediated inflammatory disorders are non-autoimmune IL-6-mediated inflammatory disorders. In specific embodiments, the patient has an IL-6-mediated disorder other than rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, or systemic juvenile idiopathic arthritis.

[0103] 2.6.4. Kidney disease In various embodiments, the patient has a kidney disease. In some embodiments, the kidney disease is chronic kidney disease (CKD).

[0104] In some embodiments, the patient has KDOQI stage 1-5 chronic kidney disease. In some embodiments, the patient has KDOQI stage 3-5 chronic kidney disease. In some embodiments, the patient has KDOQI stage 1 chronic kidney disease, KDOQI stage 2 chronic kidney disease, KDOQI stage 3 chronic kidney disease, KDOQI stage 4 chronic kidney disease, or KDOQI stage 5 chronic kidney disease. In one embodiment, the patient has KDOQI stage 5 chronic kidney disease.

[0105] In some embodiments, the patient is undergoing dialysis. In some embodiments, the patient is not undergoing dialysis. In one embodiment, the patient has KDOQI stage 3-5 chronic kidney disease and is not undergoing dialysis. In one embodiment, the patient has KDOQI stage 5 chronic kidney disease and is undergoing dialysis.

[0106] In some embodiments, the patient has cardiorenal syndrome (CRS). In some embodiments, the patient has CRS type 4.

[0107] In some embodiments, the patient has been treated with dialysis.

[0108] 2.6.5.Cardiovascular disease In various embodiments, the patient has a cardiovascular disease.

[0109] In some embodiments, the patient has a history of myocardial infarction. In certain embodiments, the patient has a history of myocardial infarction and has a CRP level of 2 mg / L or higher.

[0110] In one embodiment, the patient had a myocardial infarction within 60 days prior to the first dose of the IL-6 antagonist. In a specific embodiment, the patient had a myocardial infarction within 30 days, 14 days, 7 days, 48 ​​hours, or 24 hours prior to the first dose of the IL-6 antagonist.

[0111] In some embodiments, the patient has atherosclerosis but has never had a myocardial infarction. In certain embodiments, the patient has atherosclerosis, has never had a myocardial infarction, and has a CRP level of 2 mg / L or higher.

[0112] In some embodiments, the cardiovascular disease is congestive heart failure (CHF). In certain embodiments, the patient has congestive heart failure (CHF) with a reduced ejection fraction. In certain embodiments, the patient has congestive heart failure (CHF) with a moderate ejection fraction. In certain embodiments, the patient has congestive heart failure (CHF) with a preserved ejection fraction.

[0113] In various embodiments, 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 entire disclosure of which is incorporated herein by reference.

[0114] In some embodiments, the cardiovascular disease is diuretic resistant heart failure. Diuretic resistant heart failure is described in WO 2018 / 144773, the entire disclosure of which is incorporated herein by reference.

[0115] In some embodiments, the cardiovascular disease is acute coronary syndrome.

[0116] In certain embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce non-fatal myocardial infarction, non-fatal 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.

[0117] 2.6.6. Anemia In various embodiments, the patient has anemia.

[0118] In some embodiments, the patient has anemia of chronic disease. In some embodiments, the patient has iron refractory iron deficiency anemia (IRIDA).

[0119] In some of these embodiments, the patient may have been treated with an erythropoiesis-stimulating agent (ESA). In some embodiments, the patient may have been treated with iron supplementation. In some embodiments, the patient may have been treated with blood or packed red blood cell transfusions.

[0120] In some embodiments, IL-6 antagonists are administered in doses sufficient to reverse functional iron deficiency.

[0121] 2.6.7. Diabetes In some embodiments, the patient has diabetes. In one embodiment, the patient has type II diabetes. In one embodiment, the patient has insulin-resistant diabetes.

[0122] 2.6.8. Liver Diseases In some embodiments, the patient has liver disease. In one embodiment, the patient has non-alcoholic steatohepatitis (NASH).

[0123] 2.6.9. Osteoporosis In some embodiments, the patient has osteoporosis.

[0124] 2.6.10. Depression In some embodiments, the patient has depression.

[0125] 2.6.11. Asthma In some embodiments, the patient has asthma.

[0126] 2.6.12. Neuroinflammatory disorders In some embodiments, the patient has a 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).

[0127] 2.6.13. Age-related macular degeneration In some embodiments, the patient has age-related macular degeneration (AMD).

[0128] 2.6.14. Cancer In various embodiments, the patient has cancer.

[0129] In some embodiments, cancer is selected from the group consisting of solid tumors, small cell lung cancer, non-small cell lung cancer, hematological malignancies, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), lymphoma, and Hodgkin lymphoma.

[0130] 2.6.15 Skin diseases In various embodiments, the patient has a skin condition such as atopic dermatitis or psoriasis.

[0131] 2.6.16 Aging In some embodiments, the method prevents aging in patients.

[0132] 2.7. IL-6 Antagonist The IL-6 antagonists used in the methods described herein can reduce the biological activity of IL-6.

[0133] 2.7.1. Anti-IL-6 antibody In various embodiments, the IL-6 antagonist is an anti-IL-6 antibody, its antigen-binding fragment, or a derivative thereof.

[0134] In typical embodiments, anti-IL-6 antibodies neutralize the biological activity of IL-6. In some embodiments, neutralizing antibodies inhibit the binding of IL-6 to the IL-6 receptor.

[0135] In some embodiments, the IL-6 antagonist is an anti-IL-6 monoclonal antibody. In some embodiments, the IL-6 antagonist is a polyclonal composition comprising multiple species of anti-IL-6 antibodies, each having its own unique CDR.

[0136] In some embodiments, the anti-IL-6 antibody is Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, a single-chain antibody molecule, a bivariable domain antibody, a single variable domain antibody, a linear antibody, or a V-domain antibody.

[0137] In some embodiments, the anti-IL-6 antibody comprises a scaffold. In some embodiments, the scaffold is Fc, optionally human Fc. In some embodiments, the anti-IL-6 antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In some embodiments, the anti-IL-6 antibody comprises a heavy chain constant region of class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

[0138] In some embodiments, the IL-6 antagonist is an immunoconjugate or fusion protein containing an IL-6 antigen-binding fragment.

[0139] In some embodiments, the antibody is bispecific or multispecific, with at least one antigen-binding moiety having specificity for IL-6.

[0140] In some embodiments, the antibody is entirely human. In some embodiments, the antibody is humanized. In some embodiments, the antibody is a chimeric antibody having non-human V region and human C region domains. In some embodiments, the antibody is mouse.

[0141] In a typical embodiment, the anti-IL-6 antibody has a K2-100 nM rating for binding to human IL-6. DIn some embodiments, the anti-IL-6 antibody has a K content of 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or less than 10 nM for binding to human IL-6. D It has the following characteristics. In certain embodiments, the anti-IL-6 antibody has a K content of 5nM, 4nM, 3nM, or less than 2nM for binding to human IL-6. D It has the following characteristics. In the selected embodiment, the anti-IL-6 antibody has a K content of 1 nM, 750 pM, or less than 500 pM for binding to human IL-6. D It has the following characteristics. In certain embodiments, the anti-IL-6 antibody has a K content of 500 pM, 400 pM, 300 pM, 200 pM, or less than 100 pM for binding to human IL-6. D It holds.

[0142] In a typical embodiment, the anti-IL-6 antibody has an intravenous elimination half-life of at least 7 days. In a certain embodiment, the anti-IL-6 antibody has an elimination half-life of at least 14 days, at least 21 days, or at least 30 days.

[0143] In some embodiments, the anti-IL-6 antibody has a human IgG constant domain having at least one amino acid substitution that extends the serum half-life compared to an unsubstituted human IgG constant domain.

[0144] In one embodiment, the IgG constant domain includes substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is a tyrosine substitution, the amino acid substitution at amino acid residue 254 is a threonine substitution, and the amino acid substitution at amino acid residue 256 is a glutamic acid substitution ("YTE"). See U.S. Patent No. 7,083,784, which is incorporated herein by reference in its entirety. In one extended half-life embodiment, the IgG constant domain includes 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)).

[0145] In some embodiments, the efflux half-life of anti-IL-6 antibodies is increased by utilizing the FcRN binding properties of human serum albumin. In one embodiment, the antibody is conjugated to albumin (Smith et al., Bioconjug. Chem., 12:750-756 (2001)). In some embodiments, the anti-IL-6 antibody is fused to the bacterial albumin-binding domain (Stork et al., Prot. Eng. Design Science 20:569-76 (2007)). In some embodiments, the anti-IL-6 antibody is fused to an albumin-binding peptide (Nguygen et al., Prot Eng Design Sel 19:291-297 (2006)). In some embodiments, the anti-IL-6 antibody is bispecific, with one specificity being specific to IL-6 and the other specificity being specific to human serum albumin (Ablynx, International Publication No. 2006 / 122825 (Bispecific Nanobody)).

[0146] In some embodiments, the efflux half-life of anti-IL-6 antibodies 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 homoamino acid polymers (HAPs; HAP-modified) (Schlapschy et al., Prot Eng Design Sel 20:273-284 (2007)); or by polysialylation (Constantinou et al., Bioconjug. Chem. 20:924-931 (2009)).

[0147] 2.7.1.1. COR-001 and derivatives In one preferred embodiment, the anti-IL-6 antibody or its antigen-binding moiety comprises all six CDRs of COR-001. The COR-001 antibody (also known as MEDI5117) is described in International Publication 2010 / 088444 and U.S. Patent Publication 2012 / 0034212, the entire disclosure of which is incorporated herein by reference. In a particular embodiment, the antibody or its antigen-binding moiety comprises the COR-001 heavy chain V region and light chain V region. In a particular embodiment, the antibody is a full-length COR-001 antibody. The COR-001 antibody has the following CDRs as well as heavy chain and light chain sequences. [ka] [ka]

[0148] In various embodiments, the anti-IL-6 antibody is a derivative of COR-001.

[0149] In some embodiments, the COR-001 derivative comprises one or more amino acid substitutions in the COR-001 heavy and / or light chain V regions.

[0150] In certain embodiments, the COR-001 derivative retains specificity for human IL-6 while having 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 compared to the original V H and / or V L of the COR-001 anti-IL-6 antibody.

[0151] In certain embodiments, 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 sequences of the V H and V L domains of COR-001. Percent sequence identity is determined using the BLAST algorithm with default parameters.

[0152] In certain embodiments, the COR-001 derivative comprises an amino acid sequence that comprises an amino acid sequence in which the CDRs are 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 sequences of the respective CDRs of COR-001. Percent sequence identity is determined using the BLAST algorithm with default parameters.

[0153] In certain embodiments, V H and / or V LCDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to human IL-6).

[0154] 2.7.1.2. Siltuximab and derivatives In one embodiment, the anti-IL-6 antibody or its antigen-binding moiety comprises all six CDRs of siltuximab. In a particular embodiment, the antibody or its antigen-binding moiety comprises the siltuximab heavy chain V region and light chain V region. In a particular embodiment, the antibody is a full-length siltuximab antibody.

[0155] In various embodiments, the anti-IL-6 antibody is a derivative of siltuximab.

[0156] In some embodiments, the siltuximab derivative comprises one or more amino acid substitutions in the V region of the siltuximab heavy chain and / or light chain.

[0157] In one embodiment, the siltuximab derivative retains specificity for human IL-6 while being similar to the original siltuximab anti-IL-6 antibody. H and / or V L Compared to, it includes 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 one amino acid substitution.

[0158] In one embodiment, the siltuximab derivative is V of siltuximab. H and V LIt contains 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 domain. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0159] In one embodiment, the siltuximab derivative comprises an amino acid sequence in which the CDR 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 each CDR of siltuximab. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0160] In one embodiment, V H and / or V L CDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to human IL-6).

[0161] 2.7.1.3. Gerilimuzumab and its derivatives In one embodiment, the anti-IL-6 antibody or its antigen-binding moiety comprises all six CDRs of gerimumuzumab. In a particular embodiment, the antibody or its antigen-binding moiety comprises the gerimumuzumab heavy chain V region and light chain V region. In a particular embodiment, the antibody is a full-length gerimumuzumab antibody.

[0162] In various embodiments, the anti-IL-6 antibody is a derivative of gerimimuzumab.

[0163] In some embodiments, the gelilimuzumab derivative contains one or more amino acid substitutions in the gelilimuzumab heavy chain and / or light chain V region.

[0164] In one embodiment, a gelilimuzumab derivative retains specificity for human IL-6 while being similar to the original gelilimuzumab anti-IL-6 antibody. H and / or V L Compared to, it includes 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 one amino acid substitution.

[0165] In one embodiment, the gelilimuzumab derivative is a V of gelilimuzumab. H and V L It contains 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 domain. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0166] In one embodiment, the gerimumuzumab derivative comprises an amino acid sequence in which the CDR 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 each CDR of gerimumuzumab. Percent sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0167] In one embodiment, V H and / or V LCDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to human IL-6).

[0168] 2.7.1.4. Silkumab and its derivatives In one embodiment, the anti-IL-6 antibody or its antigen-binding moiety comprises all six CDRs of silkumab. In a particular embodiment, the antibody or its antigen-binding moiety comprises the heavy chain V region and the light chain V region of silkumab. In a particular embodiment, the antibody is a full-length silkumab antibody.

[0169] In various embodiments, the anti-IL-6 antibody is a derivative of silkumab.

[0170] In some embodiments, the silkumab derivative includes one or more amino acid substitutions in the V region of the silkumab heavy chain and / or light chain.

[0171] In one embodiment, the silkumab derivative retains specificity for human IL-6 while being similar to the original silumab anti-IL-6 antibody. H and / or V L Compared to, it includes 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 one amino acid substitution.

[0172] In one embodiment, the silkumab derivative is a V of silkumab. H and V L It contains 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 domain. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0173] In one embodiment, the silkumab derivative comprises an amino acid sequence in which the CDR 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 each silkumab CDR. Percent sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0174] In one embodiment, V H and / or V L CDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to human IL-6).

[0175] 2.7.1.5. Clazakizumab and its derivatives In one embodiment, the anti-IL-6 antibody or its antigen-binding moiety comprises all six CDRs of clazakizumab. In a particular embodiment, the antibody or its antigen-binding moiety comprises the clazakizumab heavy chain V region and light chain V region. In a particular embodiment, the antibody is a full-length clazakizumab antibody.

[0176] In various embodiments, the anti-IL-6 antibody is a derivative of crazakizumab.

[0177] In some embodiments, the crazakizumab derivative contains one or more amino acid substitutions in the V region of the crazakizumab heavy chain and / or light chain.

[0178] In one embodiment, a crazakizumab derivative retains specificity for human IL-6 while being similar to the original crazakizumab anti-IL-6 antibody. H and / or V LCompared to, it includes 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 one amino acid substitution.

[0179] In one embodiment, the crazakizumab derivative is V of crazakizumab. H and V L It contains 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 domain. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0180] In one embodiment, the crazakizumab derivative comprises an amino acid sequence in which the CDR 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 each crazakizumab CDR. Percent sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0181] In one embodiment, V H and / or V L CDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to human IL-6).

[0182] 2.7.1.6. Olokizumab and its derivatives In one embodiment, the anti-IL-6 antibody or its antigen-binding moiety comprises all six CDRs of olokizumab. In a particular embodiment, the antibody or its antigen-binding moiety comprises the olokizumab heavy chain V region and light chain V region. In a particular embodiment, the antibody is a full-length olokizumab antibody.

[0183] In various embodiments, the anti-IL-6 antibody is a derivative of olokizumab.

[0184] In some embodiments, the olokizumab derivative contains one or more amino acid substitutions in the olokizumab heavy chain and / or light chain V region.

[0185] In one embodiment, the olokizumab derivative retains specificity for human IL-6 while being similar to the original olokizumab anti-IL-6 antibody. H and / or V L Compared to, it includes 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 one amino acid substitution.

[0186] In one embodiment, the olokizumab derivative is V of olokizumab. H and V L It contains 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 domain. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0187] In one embodiment, the olokizumab derivative includes an amino acid sequence in which the CDR 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 each olokizumab CDR. Percent sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0188] In one embodiment, V H and / or V L CDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to human IL-6).

[0189] 2.7.1.7. Other anti-IL-6 antibodies and derivatives In one embodiment, the anti-IL-6 antibody or its antigen-binding moiety 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. In a particular embodiment, the antibody or its antigen-binding moiety comprises the heavy chain V region and the 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. In a particular embodiment, 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.

[0190] In various embodiments, 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.

[0191] 2.7.2. Anti-IL-6 receptor antibodies In various embodiments, the IL-6 antagonist is an anti-IL-6 receptor (anti-IL-6R) antibody, its antigen-binding fragment, or a derivative thereof.

[0192] In a typical embodiment, anti-IL-6R reduces the biological activity of the IL-6 receptor.

[0193] In some embodiments, 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 anti-IL-6R antibody species, each having a unique CDR.

[0194] In some embodiments, the anti-IL-6R antibody is Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, a single-chain antibody molecule, a bivariable domain antibody, a single variable domain antibody, a linear antibody, or a V-domain antibody.

[0195] In some embodiments, the anti-IL-6R antibody includes a scaffold. In some embodiments, the scaffold is Fc, optionally human Fc. In some embodiments, the anti-IL-6R antibody includes a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In some embodiments, the anti-IL-6R antibody includes a heavy chain constant region of class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

[0196] In some embodiments, the IL-6 antagonist is an immunoconjugate or fusion protein containing an IL-6R antigen-binding fragment.

[0197] In some embodiments, the antibody is bispecific or multispecific, with at least one antigen-binding moiety having specificity for the IL-6 receptor.

[0198] In some embodiments, the antibody is entirely human. In some embodiments, the antibody is humanized. In some embodiments, the antibody is a chimeric antibody having non-human V region and human C region domains. In some embodiments, the antibody is mouse.

[0199] In a typical embodiment, the anti-IL-6R antibody has a K2-100 nM rating for binding to the human IL-6 receptor. D It has the following characteristics. In some embodiments, the anti-IL-6R antibody has a K content of 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or less than 10 nM for binding to the human IL-6 receptor. D It has the following characteristics. In certain embodiments, the anti-IL-6R antibody has a K content of 5nM, 4nM, 3nM, or less than 2nM for binding to the human IL-6 receptor. D It has the following characteristics. In the selected embodiment, the anti-IL-6R antibody has a K content of 1 nM, 750 pM, or less than 500 pM for binding to the human IL-6 receptor. D It has the following characteristics. In certain embodiments, the anti-IL-6R antibody has a K of 500 pM, 400 pM, 300 pM, 200 pM, or less than 100 pM for binding to the human IL-6 receptor. D It holds.

[0200] In a typical embodiment, the anti-IL-6R antibody has an intravenous elimination half-life of at least 7 days. In a certain embodiment, the anti-IL-6R antibody has an elimination half-life of at least 14 days, at least 21 days, or at least 30 days.

[0201] In some embodiments, the anti-IL-6R antibody has a human IgG constant domain having at least one amino acid substitution that extends the serum half-life compared to the unsubstituted human IgG constant domain.

[0202] In one embodiment, the IgG constant domain includes substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is a tyrosine substitution, the amino acid substitution at amino acid residue 254 is a threonine substitution, and the amino acid substitution at amino acid residue 256 is a glutamic acid substitution ("YTE"). See U.S. Patent No. 7,083,784, which is incorporated herein by reference in its entirety. In one extended half-life embodiment, the IgG constant domain includes 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)).

[0203] In some embodiments, the efflux half-life of anti-IL-6R antibodies is increased by utilizing the FcRN binding properties of human serum albumin. In one embodiment, the antibody is conjugated to albumin (Smith et al., Bioconjug. Chem., 12:750-756 (2001)). In some embodiments, the anti-IL-6R antibody is fused to the bacterial albumin-binding domain (Stork et al., Prot. Eng. Design Science 20:569-76 (2007)). In some embodiments, the anti-IL-6R antibody is fused to an albumin-binding peptide (Nguygen et al., Prot Eng Design Sel 19:291-297 (2006)). In some embodiments, the anti-IL-6R antibody is bispecific, with one specificity being specific to the IL-6 receptor and the other specificity being specific to human serum albumin (Ablynx, International Publication No. 2006 / 122825 (Bispecific Nanobody)).

[0204] In some embodiments, the efflux half-life of anti-IL-6R antibodies is increased by PEGylation (Melmed et al., Nature Reviews Drug Discovery 7:641-642 (2008)); HPMA copolymer conjugation (Lu et al., Nature Biotechnology 17:1101-1104 (1999)); dextran conjugation (Nuclear Medicine Communications, 16:362-369 (1995)); conjugation with homoamino acid polymers (HAPs; HAP-modified) (Schlapschy et al., Prot Eng Design Sel 20:273-284 (2007)); or polysialylation (Constantinou et al., Bioconjug. Chem. 20:924-931 (2009)).

[0205] 2.7.2.1. Tocilizumab and derivatives In one embodiment, the anti-IL-6R antibody or its antigen-binding moiety comprises all six CDRs of tocilizumab. In a particular embodiment, the antibody or its antigen-binding moiety comprises the tocilizumab heavy chain V region and light chain V region. In a particular embodiment, the antibody is a full-length tocilizumab antibody.

[0206] In various embodiments, the anti-IL-6R antibody is a derivative of tocilizumab.

[0207] In some embodiments, the tocilizumab derivative contains one or more amino acid substitutions in the tocilizumab heavy chain and / or light chain V region.

[0208] In one embodiment, the tocilizumab derivative retains specificity for the human IL-6 receptor while being similar to the original tocilizumab anti-IL-6R antibody. H and / or V LCompared to, it includes 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 one amino acid substitution.

[0209] In one embodiment, the tocilizumab derivative is V of tocilizumab. H and V L It contains 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 domain. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0210] In one embodiment, the tocilizumab derivative includes an amino acid sequence in which the CDR 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 each tocilizumab CDR. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0211] In one embodiment, V H and / or V L CDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to the human IL-6 receptor).

[0212] 2.7.2.2. Sarilumab and its derivatives In one embodiment, the anti-IL-6R antibody or its antigen-binding moiety comprises all six CDRs of sarilumab. In a particular embodiment, the antibody or its antigen-binding moiety comprises the sarilumab heavy chain V region and light chain V region. In a particular embodiment, the antibody is a full-length sarilumab antibody.

[0213] In various embodiments, the anti-IL-6R antibody is a derivative of sarilumab.

[0214] In some embodiments, the sarilumab derivative includes one or more amino acid substitutions in the sarilumab heavy chain and / or light chain V region.

[0215] In one embodiment, the sarilumab derivative retains specificity for the human IL-6 receptor while being similar to the original sarilumab anti-IL-6R antibody. H and / or V L Compared to, it includes 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 one amino acid substitution.

[0216] In one embodiment, the sarilumab derivative is V of sarilumab. H and V L It contains 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 domain. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0217] In one embodiment, the sarilumab derivative comprises an amino acid sequence in which the CDR 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 each CDR of sarilumab. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0218] In one embodiment, V H and / or V L CDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to the human IL-6 receptor).

[0219] 2.7.2.3. Bovalilizumab and its derivatives In one embodiment, the anti-IL-6R antibody or its antigen-binding moiety includes all six CDRs of bovalilizumab. In a particular embodiment, the antibody or its antigen-binding moiety includes the bovalilizumab heavy chain V region and light chain V region. In a particular embodiment, the antibody is a full-length bovalilizumab antibody.

[0220] In various embodiments, the anti-IL-6R antibody is a derivative of bovalilizumab.

[0221] In some embodiments, the bovalilizumab derivative contains one or more amino acid substitutions in the bovalilizumab heavy chain and / or light chain V region.

[0222] In one embodiment, a bovalilizumab derivative retains specificity for the human IL-6 receptor while possessing the same characteristics as the original bovalilizumab anti-IL-6R antibody. H and / or V LCompared to, it includes 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 one amino acid substitution.

[0223] In one embodiment, the bovalilizumab derivative is a V of bovalilizumab. H and V L It contains 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 domain. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0224] In one embodiment, a bovalilizumab derivative includes an amino acid sequence in which the CDR 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 each CDR of bovalilizumab. Percentage sequence identity is determined using the BLAST algorithm with initial setting parameters.

[0225] In one embodiment, V H and / or V L CDR derivatives contain one or more conserved amino acid substitutions in the expected non-essential amino acid residues (i.e., amino acid residues that are not essential for the antibody to specifically bind to the human IL-6 receptor).

[0226] 2.7.2.4. Other anti-IL-6R antibodies and derivatives In one embodiment, the anti-IL-6R antibody or its antigen-binding moiety comprises all six CDRs of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (NovImmune), and the antibody described in U.S. Patent Publication No. 2012 / 0225060. In a particular embodiment, the antibody or its antigen-binding moiety comprises the heavy chain V region and the light chain V region of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (NovImmune), and the antibody described in U.S. Patent Publication No. 2012 / 0225060. In a particular embodiment, the antibody is full length selected from the group consisting of: SA237 (Roche), NI-1201 (NovImmune), and the antibody described in U.S. Patent Publication No. 2012 / 0225060.

[0227] In various embodiments, the anti-IL-6R antibody is a derivative of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (NovImmune), or the antibody described in U.S. Patent Publication No. 2012 / 0225060.

[0228] 2.7.3. Anti-IL-6:IL-6R conjugated antibody In various embodiments, the IL-6 antagonist is an antibody specific to the IL-6-IL-6R complex. In one embodiment, the antibody has six CDRs of an antibody selected from those described in U.S. Patent Publication 2011 / 0002936, which is incorporated herein in its entirety by reference.

[0229] 2.7.4. JAK and STAT Inhibitors In various embodiments, IL-6 antagonists are inhibitors of the JAK signaling pathway. In some embodiments, the JAK inhibitor is a JAK1-specific inhibitor. In some embodiments, the JAK inhibitor is a JAK3-specific inhibitor. In some embodiments, the JAK inhibitor is a pan-JAK inhibitor.

[0230] In one embodiment, the JAK inhibitor is selected from the group consisting of tofacitinib (Xeljanz), desernotinib, ruxolitinib, upadacitinib, baricitinib, filgotinib, restaurtinib, pacritinib, peficitinib, INCB-039110, ABT-494, INCB-047986, and AC-410.

[0231] In various embodiments, the IL-6 antagonist is a STAT3 inhibitor. In certain embodiments, this inhibitor is AZD9150 (AstraZeneca, Isis Pharmaceuticals), a STAT3 antisense molecule.

[0232] 2.7.5. Further IL-6 Antagonists In various embodiments, the IL-6 antagonist is an antagonist peptide.

[0233] In some embodiments, the IL-6 antagonist is C326 (an IL-6 inhibitor by Avidia, also known as AMG220) or FE301, a recombinant IL-6 protein inhibitor (Ferring International Center SA, Conaris Research Institute AG). In some embodiments, the anti-IL-6 antagonist includes soluble gp130, FE301 (Conaris / Ferring).

[0234] 2.8. Pharmaceutical Compositions The IL-6 antagonists used in the methods described herein can be formulated in any suitable pharmaceutical composition for administration by any suitable route of administration. Suitable routes of administration include, but are not limited to, intravitreous, intra-arterial, intradermal, intramuscular, intraperitoneal, intravenous, intranasal, parenteral, pulmonary, and subcutaneous routes.

[0235] A pharmaceutical composition may contain one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and a person skilled in the art can select a suitable pharmaceutical excipient. Therefore, the pharmaceutical excipients provided below are intended as examples only and not as an limitation. Further pharmaceutical excipients include, for example, those listed in Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), which is incorporated in whole by reference.

[0236] 2.9. Medication Plan IL-6 antagonists are administered in doses sufficient to reduce inflammation without causing immunosuppression.

[0237] 2.9.1. Antibodies, antigen-binding fragments, peptides In a typical embodiment, the antibody, antigen-binding fragment, and peptide IL-6 antagonist are administered parenterally.

[0238] In some parenteral embodiments, the IL-6 antagonist is administered intravenously. In some intravenous embodiments, the IL-6 antagonist is administered as a large, instantaneous dose. In some intravenous embodiments, the IL-6 antagonist is administered as an infusion. In some intravenous embodiments, the IL-6 antagonist is administered as an infusion after a large, instantaneous dose.

[0239] In some parenteral embodiments, IL-6 antagonists are administered subcutaneously.

[0240] In various embodiments, antibodies, antigen-binding fragments, or peptide IL-6 antagonists are administered in doses independent of the patient's body weight or surface area (uniform doses).

[0241] In some embodiments, the uniform intravenous 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 uniform intravenous 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 uniform intravenous 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 uniform intravenous dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the uniform intravenous dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the uniform intravenous dose is 200 mg, 300 mg, 400 mg, or 500 mg. In some embodiments, the uniform intravenous 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 uniform intravenous dose is 1–50 mg, 50–100 mg, or 100–500 mg.

[0242] In some embodiments, the uniform subcutaneous 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 uniform subcutaneous 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 uniform subcutaneous 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 uniform subcutaneous dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the uniform subcutaneous dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the uniform subcutaneous dose is 200 mg, 300 mg, 400 mg, or 500 mg. In some embodiments, the uniform subcutaneous 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 uniform subcutaneous dose is 1-50 mg, 50-100 mg, or 100-500 mg.

[0243] In various embodiments, antibodies, antigen-binding fragments, or peptide IL-6 antagonists are administered in doses based on the patient's body weight.

[0244] In some embodiments, the antagonist is administered in intravenous doses 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 in intravenous doses 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 in intravenous doses 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.

[0245] In some embodiments, the antagonist is administered in subcutaneous doses 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 in subcutaneous doses 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 in subcutaneous doses 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.

[0246] In various intravenous embodiments, IL-6 antagonists are administered every 7 days, every 14 days, every 21 days, every 28 days, or once a month. In various subcutaneous embodiments, IL-6 antagonists are administered every 14 days, every 28 days, once a month, every two months (every other month), or once every three months.

[0247] 2.9.2. Small molecule inhibitors In a typical embodiment, small molecule JAK inhibitors and STAT inhibitors are administered orally.

[0248] In various embodiments, the inhibitor is administered orally once or twice daily in doses 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 daily in doses of 50–60 mg, 60–70 mg, 70–80 mg, 80–90 mg, or 90–100 mg. In some embodiments, the inhibitor is administered orally once or twice daily in doses of 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg. In some embodiments, the inhibitor is administered orally once or twice daily in doses of 75 mg or 100 mg.

[0249] 2.9.3. One month equivalent dose In a typical embodiment, the IL-6 antagonist is administered at a monthly equivalent dose that is less than the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. "Monthly equivalent dose" refers to the calculated total dose administered per month, regardless of dosage or administration schedule.

[0250] In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of 50% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In various embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% or less of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In one embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of 45% or less of the monthly equivalent dose used to treat rheumatoid arthritis. In one embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of 40% or less of the monthly equivalent dose used to treat rheumatoid arthritis. In one embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of 30% or less of the monthly equivalent dose used to treat rheumatoid arthritis. In one embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of 25% or less of the monthly equivalent dose used to treat rheumatoid arthritis. In another embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of 20% or less of the monthly equivalent dose used to treat rheumatoid arthritis. In yet another embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of 15% or less of the monthly equivalent dose used to treat rheumatoid arthritis. In yet another embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of 10% or less of the monthly equivalent dose used to treat rheumatoid arthritis. In yet another embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of 5% or less of the monthly equivalent dose used to treat rheumatoid arthritis.

[0251] In various embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the monthly equivalent dose used to treat rheumatoid arthritis with the same IL-6 antagonist. In one embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 50% of the monthly equivalent dose used to treat rheumatoid arthritis. In another embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 40% of the monthly equivalent dose used to treat rheumatoid arthritis. In yet another embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 30% of the monthly equivalent dose used to treat rheumatoid arthritis. In yet another embodiment, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 25% of the monthly equivalent dose used to treat rheumatoid arthritis. In one embodiment, the IL-6 antagonist is administered at a monthly dose equivalent to about 20% of the monthly dose used to treat rheumatoid arthritis. In another embodiment, the IL-6 antagonist is administered at a monthly dose equivalent to about 15% of the monthly dose used to treat rheumatoid arthritis. In yet another embodiment, the IL-6 antagonist is administered at a monthly dose equivalent to about 10% of the monthly dose used to treat rheumatoid arthritis. In yet another embodiment, the IL-6 antagonist is administered at a monthly dose equivalent to about 5% of the monthly dose used to treat rheumatoid arthritis.

[0252] In some embodiments, the IL-6 antagonist is the COR-001 antibody. In various embodiments, COR-001 is available in doses of 0.5 to 50 mg, for example, 0.5 to 1 mg, 0.5 to 2 mg, 0.5 to 5 mg, 0.5 to 10 mg, 0.5 to 20 mg, 0.5 to 30 mg, 0.5 to 40 mg, 1 to 2 mg, 1 to 5 mg, 1 to 10 mg, 1 to 20 mg, 1 to 30 mg, 1 to 40 mg, 1 to 50 mg, 2 to 5 mg, 2 to 10 mg, 2 to 20 mg It is administered intravenously in a monthly equivalent dose of 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. In one preferred embodiment, COR-001 is administered intravenously in a monthly equivalent dose of 2-40 mg.

[0253] In various embodiments, COR-001 is administered intravenously in monthly equivalent doses of approximately 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. In one embodiment, COR-001 is administered intravenously in monthly equivalent doses of approximately 1 mg. In one embodiment, COR-001 is administered intravenously in monthly equivalent doses of approximately 2 mg. In one embodiment, COR-001 is administered intravenously in monthly equivalent doses of approximately 3 mg. In one embodiment, COR-001 is administered intravenously in monthly equivalent doses of approximately 4 mg. In one embodiment, COR-001 is administered intravenously in monthly equivalent doses of approximately 5 mg. In one embodiment, COR-001 is administered intravenously in monthly equivalent doses of approximately 6 mg. In one embodiment, COR-001 is administered intravenously in monthly equivalent doses of approximately 10 mg. In one embodiment, COR-001 is administered intravenously at a monthly dose of approximately 12 mg. In another embodiment, COR-001 is administered intravenously at a monthly dose of approximately 15 mg. In yet another embodiment, COR-001 is administered intravenously at a monthly dose of approximately 20 mg. In yet another embodiment, COR-001 is administered intravenously at a monthly dose of approximately 40 mg.

[0254] In various embodiments, COR-001 is available in doses of 1-100 mg, for example, 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, 3-10 It is administered subcutaneously in a monthly equivalent dose of 0 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. In one preferred embodiment, COR-001 is administered subcutaneously in a monthly equivalent dose of 3-70 mg.

[0255] In various embodiments, COR-001 is administered subcutaneously in monthly equivalent doses of approximately 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. In one embodiment, COR-001 is administered subcutaneously in monthly equivalent doses of approximately 1 mg. In one embodiment, COR-001 is administered subcutaneously in monthly equivalent doses of approximately 2 mg. In one embodiment, COR-001 is administered subcutaneously in monthly equivalent doses of approximately 3 mg. In one embodiment, COR-001 is administered subcutaneously in monthly equivalent doses of approximately 4 mg. In one embodiment, COR-001 is administered subcutaneously in monthly equivalent doses of approximately 5 mg. In one embodiment, COR-001 is administered subcutaneously in monthly equivalent doses of approximately 6 mg. In one embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 10 mg. In another embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 12 mg. In another embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 15 mg. In another embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 17 mg. In another embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 20 mg. In another embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 35 mg. In another embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 40 mg. In another embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 70 mg. In another embodiment, COR-001 is administered subcutaneously at a monthly dose equivalent to approximately 100 mg.

[0256] In some embodiments, the IL-6 antagonist is siltuximab. In various embodiments, siltuximab is available in doses of 10-500 mg, for example, 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. It is administered intravenously in monthly doses of 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, 150-200 mg, 150-300 mg, 150-400 mg, 150-500 mg, 200-300 mg, 200-400 mg, 200-500 mg, 300-400 mg, 300-500 mg, or 400-500 mg. In one preferred embodiment, siltuximab is administered intravenously at a monthly equivalent dose of 50 to 500 mg. In various embodiments, siltuximab is administered intravenously at monthly equivalent doses of approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 500 mg. In one embodiment, siltuximab is administered intravenously at a monthly equivalent dose of approximately 50 mg. In one embodiment, siltuximab is administered intravenously at a monthly equivalent dose of approximately 100 mg. In one embodiment, siltuximab is administered intravenously at a monthly equivalent dose of approximately 150 mg. In one embodiment, siltuximab is administered intravenously at a monthly equivalent dose of approximately 200 mg. In one embodiment, siltuximab is administered intravenously at a monthly equivalent dose of approximately 300 mg.In one embodiment, siltuximab is administered intravenously at a monthly dose of approximately 500 mg.

[0257] In various appropriately administered doses, siltuximab is available in doses of 50-1000 mg, for example, 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, and 100 It is administered subcutaneously in monthly equivalent doses of ~1000mg, 160~200mg, 160~240mg, 160~320mg, 160~480mg, 160~800mg, 160~1000mg, 200~240mg, 200~320mg, 200~480mg, 200~800mg, 200~1000mg, 240~320mg, 240~480mg, 240~800mg, 240~1000mg, 320~480mg, 320~800mg, 320~1000mg, 480~800mg, 480~1000mg, or 800~1000mg. In one preferred embodiment, siltuximab is administered subcutaneously in monthly equivalent doses of 80~800mg. In various embodiments, siltuximab is administered subcutaneously in monthly equivalent doses of approximately 50 mg, 80 mg, 100 mg, 160 mg, 240 mg, 320 mg, 480 mg, 800 mg, or 1000 mg. In one embodiment, siltuximab is administered subcutaneously in monthly equivalent doses of approximately 50 mg. In another embodiment, siltuximab is administered subcutaneously in monthly equivalent doses of approximately 80 mg. In another embodiment, siltuximab is administered subcutaneously in monthly equivalent doses of approximately 100 mg. In another embodiment, siltuximab is administered subcutaneously in monthly equivalent doses of approximately 160 mg. In another embodiment, siltuximab is administered subcutaneously in monthly equivalent doses of approximately 240 mg. In another embodiment, siltuximab is administered subcutaneously in monthly equivalent doses of approximately 320 mg. In another embodiment, siltuximab is administered subcutaneously in monthly equivalent doses of approximately 480 mg. In one embodiment, siltuximab is administered subcutaneously at a monthly dose of approximately 800 mg.In one embodiment, siltuximab is administered subcutaneously at a monthly dose of approximately 1000 mg.

[0258] In some embodiments, the IL-6 antagonist is gerilimuzumab. In various embodiments, gerilimuzumab is present in doses of 0.05 to 2 mg, e.g., 0.05 to 0.075 mg, 0.05 to 0.1 mg, 0.05 to 0.12 mg, 0.05 to 0.3 mg, 0.05 to 0.6 mg, 0.05 to 0.9 mg, 0.05 to 1.8 mg, 0.075 to 0.1 mg, 0.075 to 0.12 mg, 0.075 to 0.3 mg, 0.075 to 0.6 mg, 0.075 to 0.9 mg, 0.075 to 1.8 mg, 0.075 to 2 mg, 0.1 to 0.12 mg, 0. It is administered intravenously in monthly equivalent doses of 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 1.8-2 mg. In one preferred embodiment, gerilimuzumab is administered intravenously in monthly equivalent doses of 0.075-1.8 mg. In various embodiments, gerilimuzumab is administered intravenously in monthly equivalent doses of approximately 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 one embodiment, gerilimuzumab is administered intravenously in monthly equivalent doses of approximately 0.05 mg. In another embodiment, gerilimuzumab is administered intravenously in monthly equivalent doses of approximately 0.075 mg. In another embodiment, gerilimuzumab is administered intravenously in monthly equivalent doses of approximately 0.1 mg. In another embodiment, gerilimuzumab is administered intravenously in monthly equivalent doses of approximately 0.12 mg. In another embodiment, gerilimuzumab is administered intravenously in monthly equivalent doses of approximately 0.3 mg. In another embodiment, gerilimuzumab is administered intravenously in monthly equivalent doses of approximately 0.6 mg. In one embodiment, gerilimuzumab is administered intravenously at a monthly dose of approximately 0.9 mg. In another embodiment, gerilimuzumab is administered intravenously at a monthly dose of approximately 1.8 mg.In one embodiment, gerilimuzumab is administered intravenously at a monthly dose of approximately 2 mg.

[0259] In various embodiments, gerilimuzumab is administered in doses of 0.1 to 5 mg, for example, 0.1 to 0.125 mg, 0.1 to 0.15 mg, 0.1 to 0.2 mg, 0.1 to 0.5 mg, 0.1 to 1 mg, 0.1 to 1.5 mg, 0.1 to 2 mg, 0.1 to 3 mg, 0.1 to 4 mg, 0.125 to 0.15 mg, 0.125 to 0.2 mg, 0.125 to 0.5 mg, 0.125 to 1 mg, 0.125 to 1.5 mg, 0.125 to 2 mg, 0.125 to 3 mg, 0.125 to 4 mg, 0.125 to 5 mg, 0.15 to 0.2 mg, 0.15 to 0.5 mg, 0.15 to 1 mg, 0.15 to 1.5 mg, and 0.1 It is administered subcutaneously in doses equivalent to one month's dose: 5-2 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, 1.5-2 mg, 1.5-3 mg, 1.5-4 mg, 1.5-5 mg, 2-3 mg, 2-4 mg, 2-5 mg, 3-4 mg, 3-5 mg, or 4-5 mg. In one preferred embodiment, gerimumuzumab is administered subcutaneously at a monthly equivalent dose of 0.125 to 3 mg. In various embodiments, gerimumuzumab is administered subcutaneously at a monthly equivalent dose of approximately 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 one embodiment, gerimumuzumab is administered subcutaneously at a monthly equivalent dose of approximately 0.125 mg. In one embodiment, gerimumuzumab is administered subcutaneously at a monthly equivalent dose of approximately 0.2 mg. In one embodiment, gerimumuzumab is administered subcutaneously at a monthly equivalent dose of approximately 0.5 mg. In one embodiment, gerimumuzumab is administered subcutaneously at a monthly equivalent dose of approximately 1 mg. In one embodiment, gerimumuzumab is administered subcutaneously at a monthly equivalent dose of approximately 1.5 mg. In one embodiment, gerilimuzumab is administered subcutaneously at a monthly dose of approximately 3 mg.

[0260] In some embodiments, the IL-6 antagonist is sirukmab. In various embodiments, sirukmab is administered intravenously in a monthly equivalent dose of 1 to 80 mg, for example, 1 to 1.5 mg, 1 to 3 mg, 1 to 6 mg, 1 to 12 mg, 1 to 36 mg, 1 to 60 mg, 1.5 to 3 mg, 1.5 to 6 mg, 1.5 to 12 mg, 1.5 to 36 mg, 1.5 to 60 mg, 1.5 to 80 mg, 3 to 6 mg, 3 to 12 mg, 3 to 36 mg, 3 to 60 mg, 3 to 80 mg, 6 to 12 mg, 6 to 36 mg, 6 to 60 mg, 6 to 80 mg, 12 to 36 mg, 12 to 60 mg, 12 to 80 mg, 36 to 60 mg, 36 to 80 mg, or 60 to 80 mg. In one preferred embodiment, sirukmab is administered intravenously in a monthly equivalent dose of 1.5 to 60 mg. In various embodiments, sirukmab is administered intravenously in monthly equivalent doses of approximately 1 mg, 1.5 mg, 3 mg, 6 mg, 12 mg, 36 mg, 60 mg, or 80 mg. In one embodiment, sirukmab is administered intravenously in monthly equivalent doses of approximately 1 mg. In another embodiment, sirukmab is administered intravenously in monthly equivalent doses of approximately 1.5 mg. In another embodiment, sirukmab is administered intravenously in monthly equivalent doses of approximately 3 mg. In another embodiment, sirukmab is administered intravenously in monthly equivalent doses of approximately 6 mg. In another embodiment, sirukmab is administered intravenously in monthly equivalent doses of approximately 12 mg. In another embodiment, sirukmab is administered intravenously in monthly equivalent doses of approximately 36 mg. In another embodiment, sirukmab is administered intravenously in monthly equivalent doses of approximately 60 mg. In another embodiment, sirukmab is administered intravenously in monthly equivalent doses of approximately 80 mg.

[0261] In various embodiments, silkumab is administered in doses of 1-100 mg, for example, 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, It is administered subcutaneously in monthly equivalent doses of 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. In one preferred embodiment, silkumab is administered subcutaneously in monthly equivalent doses of 2.5-100 mg. In various embodiments, sirukmab is administered subcutaneously in monthly equivalent doses of approximately 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 100 mg. In one embodiment, sirukmab is administered subcutaneously in monthly equivalent doses of approximately 2.5 mg. In one embodiment, sirukmab is administered subcutaneously in monthly equivalent doses of approximately 5 mg. In one embodiment, sirukmab is administered subcutaneously in monthly equivalent doses of approximately 10 mg. In one embodiment, sirukmab is administered subcutaneously in monthly equivalent doses of approximately 20 mg. In one embodiment, sirukmab is administered subcutaneously in monthly equivalent doses of approximately 60 mg. In one embodiment, sirukmab is administered subcutaneously in monthly equivalent doses of approximately 100 mg.

[0262] In some embodiments, the IL-6 antagonist is crazakizumab. In various embodiments, crazakizumab is administered intravenously in a monthly equivalent dose of 1 to 80 mg, for example, 1 to 3 mg, 1 to 6 mg, 1 to 12 mg, 1 to 24 mg, 1 to 36 mg, 1 to 60 mg, 3 to 6 mg, 3 to 12 mg, 3 to 24 mg, 3 to 36 mg, 3 to 60 mg, 3 to 80 mg, 6 to 12 mg, 6 to 24 mg, 6 to 36 mg, 6 to 60 mg, 6 to 80 mg, 12 to 24 mg, 12 to 36 mg, 12 to 60 mg, 12 to 80 mg, 24 to 36 mg, 24 to 60 mg, 24 to 80 mg, 36 to 60 mg, 36 to 80 mg, or 60 to 80 mg. In one preferred embodiment, crazakizumab is administered intravenously in a monthly equivalent dose of 3 to 60 mg. In various embodiments, crazakizumab is administered intravenously in monthly equivalent doses of approximately 1 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, 60 mg, or 80 mg. In one embodiment, crazakizumab is administered intravenously in monthly equivalent doses of approximately 1 mg. In another embodiment, crazakizumab is administered intravenously in monthly equivalent doses of approximately 3 mg. In another embodiment, crazakizumab is administered intravenously in monthly equivalent doses of approximately 6 mg. In another embodiment, crazakizumab is administered intravenously in monthly equivalent doses of approximately 12 mg. In another embodiment, crazakizumab is administered intravenously in monthly equivalent doses of approximately 24 mg. In another embodiment, crazakizumab is administered intravenously in monthly equivalent doses of approximately 36 mg. In another embodiment, crazakizumab is administered intravenously in monthly equivalent doses of approximately 60 mg. In one embodiment, crazakizumab is administered intravenously at a monthly dose of approximately 80 mg.

[0263] In various embodiments, crazakizumab is administered in doses of 1-100 mg, for example, 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. It is administered subcutaneously in a monthly equivalent dose of 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. In one preferred embodiment, crazakizumab is administered subcutaneously in a monthly equivalent dose of 5-100 mg. In various embodiments, crazakizumab is administered subcutaneously in monthly equivalent doses of approximately 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 100 mg. In one embodiment, crazakizumab is administered subcutaneously in monthly equivalent doses of approximately 5 mg. In another embodiment, crazakizumab is administered subcutaneously in monthly equivalent doses of approximately 10 mg. In another embodiment, crazakizumab is administered subcutaneously in monthly equivalent doses of approximately 20 mg. In another embodiment, crazakizumab is administered subcutaneously in monthly equivalent doses of approximately 40 mg. In another embodiment, crazakizumab is administered subcutaneously in monthly equivalent doses of approximately 60 mg. In another embodiment, crazakizumab is administered subcutaneously in monthly equivalent doses of approximately 100 mg.

[0264] In some embodiments, the IL-6 antagonist is olokizumab. In various embodiments, olokizumab is administered intravenously in doses of 1 to 80 mg, for example, 1 to 1.8 mg, 1 to 3.6 mg, 1 to 9 mg, 1 to 18 mg, 1 to 45 mg, 1 to 60 mg, 1.8 to 3.6 mg, 1.8 to 9 mg, 1.8 to 18 mg, 1.8 to 45 mg, 1.8 to 60 mg, 1.8 to 80 mg, 3.6 to 9 mg, 3.6 to 18 mg, 3.6 to 45 mg, 3.6 to 60 mg, 3.6 to 80 mg, 9 to 18 mg, 9 to 45 mg, 9 to 60 mg, 9 to 80 mg, 18 to 45 mg, 18 to 60 mg, 18 to 80 mg, 45 to 60 mg, 45 to 80 mg, or 60 to 80 mg, which is equivalent to a one-month dose. In one preferred embodiment, olokizumab is administered intravenously at a monthly equivalent dose of 1.8 to 60 mg. In various embodiments, olokizumab is administered intravenously at monthly equivalent doses of approximately 1 mg, 1.8 mg, 3.6 mg, 9 mg, 18 mg, 45 mg, 60 mg, or 80 mg. In one embodiment, olokizumab is administered intravenously at a monthly equivalent dose of approximately 1 mg. In one embodiment, olokizumab is administered intravenously at a monthly equivalent dose of approximately 1.8 mg. In one embodiment, olokizumab is administered intravenously at a monthly equivalent dose of approximately 3.6 mg. In one embodiment, olokizumab is administered intravenously at a monthly equivalent dose of approximately 9 mg. In one embodiment, olokizumab is administered intravenously at a monthly equivalent dose of approximately 18 mg. In one embodiment, olokizumab is administered intravenously at a monthly equivalent dose of approximately 45 mg. In one embodiment, olokizumab is administered intravenously at a monthly dose of approximately 60 mg. In another embodiment, olokizumab is administered intravenously at a monthly dose of approximately 80 mg.

[0265] In various embodiments, olokizumab is administered in doses of 1 to 100 mg, for example, 1 to 3 mg, 1 to 6 mg, 1 to 10 mg, 1 to 15 mg, 1 to 20 mg, 1 to 30 mg, 1 to 50 mg, 1 to 72 mg, 3 to 6 mg, 3 to 10 mg, 3 to 15 mg, 3 to 20 mg, 3 to 30 mg, 3 to 50 mg, 3 to 72 mg, 3 to 100 mg, 6 to 10 mg, 6 to 15 mg, 6 to 20 mg, 6 to 30 mg, 6 to 50 mg, 6 to 72 mg, 6 to 100 mg, It is administered subcutaneously in monthly equivalent doses of 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. In one preferred embodiment, olokizumab is administered subcutaneously in monthly equivalent doses of 3-100 mg. In various embodiments, olokizumab is administered subcutaneously in monthly equivalent doses of approximately 1 mg, 3 mg, 6 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, 72 mg, or 100 mg. In one embodiment, olokizumab is administered subcutaneously in monthly equivalent doses of approximately 3 mg. In another embodiment, olokizumab is administered subcutaneously in monthly equivalent doses of approximately 6 mg. In another embodiment, olokizumab is administered subcutaneously in monthly equivalent doses of approximately 15 mg. In another embodiment, olokizumab is administered subcutaneously in monthly equivalent doses of approximately 30 mg. In another embodiment, olokizumab is administered subcutaneously in monthly equivalent doses of approximately 72 mg. In another embodiment, olokizumab is administered subcutaneously in monthly equivalent doses of approximately 100 mg.

[0266] In some embodiments, the IL-6 antagonist is tocilizumab. Tocilizumab is available in various dosages, such as 10-500mg, 10-20mg, 10-50mg, 10-100mg, 10-150mg, 10-200mg, 10-250mg, 10-300mg, 10-350mg, 10-400mg, 20-50mg, 20-100mg, 20-150mg, 20-200mg, 20-250mg, 20-300mg, 20-350mg, 20-400mg, 20-500mg, 50-100mg, 50-150mg, 50-200mg, 50-250mg, 50-300mg, 50-350mg, 50-400mg, 50-500mg, 100-150mg, 100-200mg It is administered intravenously in doses equivalent to one month's supply, such as 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, 250-300 mg, 250-350 mg, 250-400 mg, 250-500 mg, 300-350 mg, 300-400 mg, 300-500 mg, 350-400 mg, 350-500 mg, or 400-500 mg. In one preferred embodiment, tocilizumab is administered intravenously at a monthly equivalent dose of 50 to 500 mg. In various embodiments, tocilizumab is administered intravenously at monthly equivalent doses of approximately 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 one embodiment, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 50 mg. In one embodiment, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 100 mg. In one embodiment, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 150 mg. In one embodiment, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 250 mg. In one embodiment, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 350 mg.In one embodiment, tocilizumab is administered intravenously at a monthly dose of approximately 500 mg.

[0267] In various embodiments, tocilizumab is administered in doses of 50-1000 mg, for example, 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- Tocilizumab is administered subcutaneously in monthly equivalent doses of 400 mg, 160-560 mg, 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. In one preferred embodiment, tocilizumab is administered subcutaneously in monthly equivalent doses of 80-800 mg. In various embodiments, tocilizumab is administered subcutaneously in monthly equivalent doses of approximately 50 mg, 80 mg, 160 mg, 240 mg, 400 mg, 560 mg, 800 mg, or 1000 mg. In one embodiment, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 50 mg. In another embodiment, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 80 mg. In another embodiment, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 160 mg. In another embodiment, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 240 mg. In another embodiment, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 400 mg. In another embodiment, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 560 mg. In another embodiment, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 800 mg. In another embodiment, tocilizumab is administered subcutaneously at a monthly dose equivalent to approximately 1000 mg.

[0268] In some embodiments, the IL-6 antagonist is sarilumab. In various embodiments, sarilumab is administered intravenously in doses of 10-150 mg, for example, 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, equivalent to a one-month dose. In one preferred embodiment, sarilumab is administered intravenously at a monthly equivalent dose of 12 to 120 mg. In various embodiments, sarilumab is administered intravenously at monthly equivalent doses of 10 mg, 12 mg, 24 mg, 48 mg, 60 mg, 72 mg, 120 mg, or 150 mg. In one embodiment, sarilumab is administered intravenously at a monthly equivalent dose of 10 mg. In one embodiment, sarilumab is administered intravenously at a monthly equivalent dose of 12 mg. In one embodiment, sarilumab is administered intravenously at a monthly equivalent dose of 24 mg. In one embodiment, sarilumab is administered intravenously at a monthly equivalent dose of 48 mg. In one embodiment, sarilumab is administered intravenously at a monthly equivalent dose of 60 mg. In one embodiment, sarilumab is administered intravenously at a monthly equivalent dose of 72 mg. In one embodiment, sarilumab is administered intravenously at a monthly equivalent dose of 120 mg. In one embodiment, sarilumab is administered intravenously at a monthly dose equivalent to 150 mg.

[0269] In various embodiments, sarilumab is administered subcutaneously in doses of 10-200 mg, for example, 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 as a monthly equivalent dose. In one preferred embodiment, sarilumab is administered subcutaneously at a monthly equivalent dose of 20 to 200 mg. In various embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, or 200 mg. In one embodiment, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 20 mg. In one embodiment, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 40 mg. In one embodiment, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 80 mg. In one embodiment, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg. In one embodiment, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 120 mg. In one embodiment, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 200 mg.

[0270] In some embodiments, the IL-6 antagonist is bovalilizumab. In various embodiments, bovalilizumab is administered intravenously in a monthly equivalent dose of 2 to 150 mg, for example, 2 to 4 mg, 2 to 6 mg, 2 to 30 mg, 2 to 60 mg, 2 to 84 mg, 2 to 120 mg, 4 to 6 mg, 4 to 30 mg, 4 to 60 mg, 4 to 84 mg, 4 to 120 mg, 4 to 150 mg, 6 to 30 mg, 6 to 60 mg, 6 to 84 mg, 6 to 120 mg, 6 to 150 mg, 30 to 60 mg, 30 to 84 mg, 30 to 120 mg, 30 to 150 mg, 60 to 84 mg, 60 to 120 mg, 60 to 150 mg, 84 to 120 mg, 84 to 150 mg, or 120 to 150 mg. In one preferred embodiment, bovalilizumab is administered intravenously at a monthly equivalent dose of 4 to 120 mg. In various embodiments, bovalilizumab is administered intravenously at monthly equivalent doses of approximately 2 mg, 4 mg, 6 mg, 30 mg, 60 mg, 84 mg, 120 mg, or 150 mg. In one embodiment, bovalilizumab is administered intravenously at a monthly equivalent dose of approximately 2 mg. In one embodiment, bovalilizumab is administered intravenously at a monthly equivalent dose of approximately 4 mg. In one embodiment, bovalilizumab is administered intravenously at a monthly equivalent dose of approximately 6 mg. In one embodiment, bovalilizumab is administered intravenously at a monthly equivalent dose of approximately 30 mg. In one embodiment, bovalilizumab is administered intravenously at a monthly equivalent dose of approximately 60 mg. In one embodiment, bovalilizumab is administered intravenously at a monthly equivalent dose of approximately 84 mg. In one embodiment, bovalilizumab is administered intravenously at a monthly dose of approximately 120 mg. In another embodiment, bovalilizumab is administered intravenously at a monthly dose of approximately 150 mg.

[0271] In various embodiments, bovalilizumab is administered in doses of 5-200 mg, for example, 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, and 10 It is administered subcutaneously in monthly equivalent doses of ~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. In one preferred embodiment, bovalilizumab is administered subcutaneously in monthly equivalent doses of 7~200 mg. In various embodiments, bovalilizumab is administered subcutaneously in monthly equivalent doses of approximately 5 mg, 7 mg, 10 mg, 20 mg, 40 mg, 50 mg, 70 mg, 100 mg, 140 mg, or 200 mg. In one embodiment, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 7 mg. In another embodiment, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 10 mg. In another embodiment, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 50 mg. In another embodiment, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 100 mg. In another embodiment, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 140 mg. In another embodiment, bovalilizumab is administered subcutaneously at a monthly dose equivalent to approximately 200 mg. [Examples]

[0272] 3. Examples The following examples are provided for illustrative purposes and demonstration purposes only, and not for limitation.

[0273] 3.1. [Example 1] Phase 1 / 2 Clinical Trial A Phase 1 / 2 clinical trial was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of multiple intravenous administrations of COR-001.

[0274] 3.1.1. Pharmaceuticals (COR-001) COR-001 is a human IgG1,κ antibody produced against interleukin-6 (IL-6). COR-001 contains the "YTE" mutation in its Fc region. The sequence and other characteristics of COR-001 are described in Chapter 2.7.1.1 above.

[0275] 3.1.2. Research design This 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 a continuous cohort of hemodialysis patients.

[0276] The main eligibility criteria include stage 5 chronic kidney disease (CKD-5) requiring hemodialysis, positivity for the TMPRSS6 736A genotype (major allele), IL-6 levels greater than 4 pg / mL, and an erythropoietin resistance index greater than 8.

[0277] Ten hemodialysis patients were randomly assigned to receive either COR-001 or placebo within each treatment cohort. When a higher dose than previously studied in a cohort was initiated, the first two patients (scouts) in that cohort (randomly assigned 1:1 to either COR-001 or placebo) were initially randomly assigned, and at least 48 hours later, the remaining patients were randomly assigned in a COR-001:placebo ratio of 7:1. The final ratio of patients treated with COR-001 to those treated with placebo was 8:2 in each cohort of 10 patients. Maximum tolerated dose (MTD) assessment was based on safety data from weeks 1 to 3. MTD was considered exceeded if more than two of the eight active patients in a cohort experienced dose-limiting toxicity (DLT).

[0278] A schematic diagram of the dose escalation is shown in Figure 1. COR-001 was administered as an intravenous infusion and started at any point before the last hour of the dialysis procedure. The COR-001 dosing schedule is shown in Table 1 below. [Table 1]

[0279] The total study period for each patient was approximately 9 months, excluding a maximum screening period of 4 weeks. As shown in Figure 2, the study included a 12-week treatment period (weeks 1-12), a 12-week safety follow-up period (weeks 13-24), and a 10-week extended follow-up period (weeks 25-35).

[0280] Descriptive statistics were used to summarize interim study data for each treatment group in appropriate analysis populations. Descriptive statistics for continuous variables included the 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.

[0281] Changes in high-sensitivity C-reactive protein (hsCRP), absolute neutrophil count (ANC), lipoprotein(a) levels, LDL levels, hemoglobin, transferrin saturation (TSAT), albumin, erythropoietin resistance index (ERI), grip strength, NT-proBNP, and cardiac MRI were recorded during the study.

[0282] 3.1.3. Analysis of Clinical Data We conducted analyses to determine the effects of COR-001 on C-reactive protein (CRP), hemoglobin levels, various cardiac parameters, and neutrophil and platelet levels.

[0283] C-reactive protein (CRP) is a marker of inflammation. CRP levels increase in response to inflammation and can be measured by the hsCRP (high-sensitivity C-reactive protein) test. hsCRP levels were measured in patients in placebo, 2 mg, 6 mg, and 20 mg dose groups over the treatment period and safety follow-up period, respectively.

[0284] At 12 weeks, the percentage of patients with a mean post-treatment hsCRP <2 mg / L was 44%, 62%, and 85% in the 2 mg, 6 mg, and 20 mg dosing regimens, respectively, compared to 14% in the placebo group. hsCRP responder analysis showed that COR-001 (anti-IL-6) had a superior effect on hsCRP compared to canakinumab (anti-IL1β) reported in the CANTOS trial. The hsCRP responder ratios for COR-001 with 20 mg and 6 mg intravenous dosing in stage 5 chronic kidney disease patients undergoing dialysis (Figure 3A) were higher than those for canakinumab at the same dose in the CANTOS trial (Figure 3B). The in vivo IC50 concentration of COR-001 for CRP (a 50% reduction from baseline CRP) was 206 ng / mL.

[0285] COR-001 improved hemoglobin levels, a key indicator of anemia. Hemoglobin responder analysis showed the dose-dependent hemoglobin responder ratio for COR-001 treatment (Figure 4).

[0286] The effects of COR-001 on various biomarkers of heart failure were determined. As shown in Figure 5, COR-001 reduced the N-terminal prohormone level of brain natriuretic peptide (NT-proBNP). The results indicate that treatment with COR-001 can reduce heart failure.

[0287] Anti-inflammatory treatments in general, particularly IL-6 inhibitor therapy, carry the risk of inducing immunosuppression, thereby promoting the development of infections that can sometimes be severe. Immunosuppression can be measured by neutrophil count. The effect of COR-001 on neutrophil count was determined.

[0288] Surprisingly, despite the significant decrease in inflammation as measured by hsCRP levels (Figure 3A), the absolute neutrophil count in patients treated with COR-001 did not decrease below normal levels. No opportunistic infections were observed during treatment. As shown in Figure 6A, 2.0 × 10⁻⁶ 9 The percentage of patients with an absolute neutrophil count below 1 / L was not increased by COR-001 at all tested doses compared to the placebo group. All patients treated with COR-001 at all tested doses were 1.5 × 10⁻⁶. 9 The patient had an absolute neutrophil count exceeding / L. The in vivo IC50 concentration of COR-001 relative to the neutrophil count (a 50% reduction in baseline neutrophil count) was 5540 ng / mL.

[0289] 100 x 10 9 The percentage of patients with platelet counts below / L was less than 30% for COR-001 for all tested doses (Figure 6B). The in vivo IC50 concentration of COR-001 relative to platelet count (50% reduction in baseline platelet count) was 13800 ng / mL.

[0290] In summary, clinical data showed that COR-001 treatment at doses of 2 mg, 6 mg, and 20 mg reduced inflammation without inducing immunosuppression in patients with stage 5 chronic kidney disease (CKD-5) undergoing dialysis, while absolute neutrophil counts did not decrease significantly in patients treated with COR-001.

[0291] Administration of COR-001 lowered CRP in a dose-dependent manner. Furthermore, COR-001 increased hemoglobin levels in these patients. COR-001 also reduced NT-proBNP, a biomarker of heart failure.

[0292] 4. Incorporation by reference All publications, patents, patent applications, and other documents cited herein are incorporated herein by reference in whole for all purposes to the same extent that each individual publication, patent, patent application, or other document is individually indicated to be incorporated by reference for all purposes.

[0293] 5. Equals While various specific embodiments have been illustrated and described, the above specification is not limiting. It will be understood that various modifications can be made without departing from the spirit and scope of the invention. Various modifications will become obvious to those skilled in the art by examining this specification.

Claims

1. A composition for treating cardiovascular disease in patients with KDOQI stage 3 to 5 chronic kidney disease, wherein the composition comprises an anti-IL-6 antibody, is administered to the patient, the anti-IL-6 antibody is COR-001, and COR-001 is administered subcutaneously at a dose of 3 to 20 mg every four weeks.

2. The composition according to claim 1 for reducing non-fatal myocardial infarction, non-fatal stroke, and cardiovascular mortality.

3. The composition according to claim 1, wherein the anti-IL-6 antibody is administered in a dose sufficient to reduce inflammation without causing immunosuppression.

4. The composition according to claim 1, wherein COR-001 is administered subcutaneously at a dose of 5 to 20 mg every four weeks.

5. The composition according to claim 1, wherein COR-001 is administered subcutaneously at a dose of 10 to 20 mg every four weeks.

6. The composition according to claim 1, wherein COR-001 is administered subcutaneously at a dose of 15 mg every four weeks.

7. The composition according to any one of claims 1 to 6, wherein the patient's pre-treatment C-reactive protein (CRP) level is at least 2 mg / L.

8. The composition according to any one of claims 1 to 7, wherein the patient's pre-treatment serum IL-6 level is at least 2 pg / mL.

9. The composition according to any one of claims 1 to 8, wherein the post-treatment CRP level is 2 mg / L or less.

10. The composition according to claim 3, wherein the immunosuppression is measured by absolute neutrophil count (ANC).

11. The composition according to claim 10, wherein the ANC after treatment is at least 1500 cells / μL.

12. The composition according to any one of claims 1 to 11, wherein the patient is not undergoing dialysis.

13. The composition according to any one of claims 1 to 12, wherein the patient has atherosclerosis.

14. The composition according to any one of claims 1 to 13, wherein the COR-001 antibody comprises the following CDR sequences: heavy chain (VH) CDR1 sequence of SEQ ID NO: 7, CDR2 sequence of SEQ ID NO: 8, and CDR3 sequence of SEQ ID NO: 9, and light chain (VL) CDR1 sequence of SEQ ID NO: 10, CDR2 sequence of SEQ ID NO: 11, and CDR3 sequence of SEQ ID NO: 12.

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