EA045389B1 - METHOD FOR TREATING CARDIOVASCULAR DISEASE - Google Patents

Description

Link to related applications

This application claims benefit from U.S. Provisional Patent Application No. 62/614,134, filed January 5, 2018, which is hereby incorporated by reference in its entirety.

List of sequences

This application contains a sequence listing that was provided via EFS-Web and is thus incorporated herein by reference in its entirety. The specified ASCII copy is named 38802US_sequence listing.txt.

BACKGROUND OF THE INVENTION

Chronic inflammation is a feature of many diseases, including classic rheumatic disorders such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis and inflammatory bowel disease, and other systemic diseases that are increasingly thought to be associated with chronic inflammation, such as cardiovascular disease. vascular disease, kidney disease, neuroinflammatory diseases, anemias, cancer and aging.

The pro-inflammatory cytokine, IL-6, often plays a critical role in chronic inflammation through activation of the JAK-STAT signaling pathway, and IL-6 inhibitors have been developed to treat certain inflammatory disorders in which IL-6 has been shown to contribute significantly. contribution to the etiology of the disease. The IL-6 receptor antibody, tocilizumab (ACTEMRA), has been approved for the treatment of rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and iatrogenic cytokine release syndrome. The IL-6 receptor antibody, sarilumab (KEVZARA), has been approved for the treatment of adult patients with moderate to severe rheumatoid arthritis.

Although IL-6 inhibition may be effective, treatment of chronic inflammation with IL-6 inhibitors using current dosing regimens often results in immunosuppression. Immunosuppression may result in increased sensitivity to pathogens such as bacteria, fungi and viruses. ACTEMRA's FDA-approved prescribing information warns of the risks of serious infections leading to hospitalization or death, including tuberculosis, bacterial infection, invasive fungal infection, viral and other opportunistic infections; The package leaflet for KEVZARA warns of serious infections leading to hospitalization or death, including bacterial, viral, invasive fungal infections and other opportunistic infections.

Thus, there is a need for new treatments for IL-6-mediated inflammation that do not lead to immunosuppression.

Brief Disclosure of the Invention

The present inventors have demonstrated that IL-6 antagonists can be administered at a dose, schedule and for a period of time that are sufficient to reduce inflammation without causing immunosuppression.

Accordingly, in a first aspect, methods are provided for treating IL-6-mediated inflammation in a patient. The methods include: administering an IL-6 antagonist to a patient with IL-6-mediated inflammation at a dose that is sufficient to reduce inflammation without causing immunosuppression. In some embodiments, the patient has elevated C-reactive protein (CRP) levels prior to treatment. 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.

In accordance with some embodiments, the patient has elevated serum levels of IL-6 prior to treatment. In some embodiments, the patient's pre-treatment serum level of IL-6 is at least 4 pg/ml. In some embodiments, the patient's pre-treatment serum level of IL-6 is at least 4 pg/ml. In some embodiments, the patient's pre-treatment serum level of IL-6 is at least 5 pg/ml. In some embodiments, the patient's pre-treatment serum level of IL-6 is at least 10 pg/ml.

In some embodiments, inflammation is measured by CRP levels. In some embodiments, the post-treatment CRP level is no more than 2 mg/L. In some embodiments, the post-treatment CRP level is no more than 1 mg/L. In some embodiments, the CRP level is reduced by at least 50% compared to pre-treatment levels. In some embodiments, the CRP level is reduced by at least 70% compared to pre-treatment levels. According to some embodiments, the level

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CRP is reduced by at least 80% compared to pre-treatment levels. In some embodiments, the CRP level is reduced by at least 90% compared to pre-treatment levels.

In some embodiments, immunosuppression is measured by 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 is reduced by no more than 2000 cells/μL compared to pre-treatment levels. In some embodiments, the ANC is reduced by no more than 1500 cells/μL compared to pre-treatment levels. In some embodiments, the ANC is reduced by no more than 1000 cells/μL compared to pre-treatment levels. In some embodiments, the ANC is reduced by no more than 500 cells/μL compared to pre-treatment levels. In some embodiments, the ANC is reduced by no more than 50% compared to pre-treatment levels. In some embodiments, ANC is reduced by no more than 40% compared to pre-treatment levels. In some embodiments, the ANC is reduced by no more than 30% compared to pre-treatment levels. In some embodiments, the ANC is reduced by no more than 20% compared to pre-treatment levels. In some embodiments, the ANC is reduced by no more than 10% compared to pre-treatment levels. In some embodiments, ANC is not reduced from pre-treatment levels.

In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 30% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 20% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 10% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 25% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 20% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 15% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 10% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is approximately 5% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.

In accordance with some embodiments, the IL-6 antagonist is an anti-IL-6 antibody.

In some embodiments, the anti-IL-6 antibody is COR001. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of 2-40 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 2 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 4 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 6 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 10 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 20 mg. In some embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 40 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of 3-70 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 3 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 7 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 10 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 17 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 35 mg. In some embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 70 mg. In some embodiments, the anti-IL-6 antibody is siltuximab. In some embodiments, siltuximab is administered intravenously at a monthly equivalent dose of 50-500 mg. In some embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 50 mg. In some embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 100 mg. In some embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 150 mg. In some embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 200 mg. In some embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 300 mg. In some embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 500 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of 80-800 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 80 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 160 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 240 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 320 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 480 mg. In some embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 800 mg.

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

In some embodiments, the anti-IL-6 antibody is sirukumab. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of 1.5-60 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 1.5 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 3 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 6 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 12 mg. In some embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 36 mg. According to some embodiments, sirukumab

- 3 045389 is administered intravenously at a monthly equivalent dose of approximately 60 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of 2.5-100 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 2.5 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 5 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 10 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 20 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 60 mg. In some embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg.

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

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

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. In accordance with some embodiments, an anti-IL-6 antibody

- 4 045389 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. 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.

In accordance with some embodiments, the IL-6 antagonist is an anti-IL-6R antibody.

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

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

In some embodiments, the anti-IL-6R antibody is vobarilizumab. In some embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of 4-120 mg. In some embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 4 mg. In some embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 6 mg. In some embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose,

- 5 045389 component of approximately 30 mg. In some embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 60 mg. In some embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 84 mg. In some embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 120 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of 7-200 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 7 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 10 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 50 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 140 mg. In some embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 200 mg.

In accordance with some embodiments, the IL-6 antagonist is a JAK inhibitor. In accordance with some embodiments, the IL-6 antagonist is a STAT3 inhibitor. In accordance with some embodiments, the patient has a hepcidin-mediated disorder.

In accordance with some embodiments, the patient has kidney disease. In accordance with some embodiments, the patient has chronic kidney disease. In some embodiments, the patient has KDOQI stage 15 chronic kidney disease. In some embodiments, the patient has KDOQI stage 3-5 chronic kidney disease. In accordance with some embodiments, the patient is not on dialysis. In some embodiments, the patient has KDOQI stage 5 chronic kidney disease. In accordance with some embodiments, the patient is on dialysis. In accordance with some embodiments, the patient has cardiorenal syndrome (CRS). In accordance with some embodiments, the patient has CRS type 4.

In accordance with some embodiments, the patient has cardiovascular disease. In accordance with some embodiments, the patient has diuretic-resistant heart failure. In accordance with some embodiments, the patient has congestive heart failure (CHF). In accordance with some embodiments, the patient has congestive heart failure (CHF) with reduced ejection fraction. In accordance with some embodiments, the patient has congestive heart failure (CHF) with intermediate ejection fraction. In accordance with some embodiments, the patient has congestive heart failure (CHF) with preserved ejection fraction. In accordance with some embodiments, the patient has an acute coronary syndrome. In accordance with some embodiments, the patient has atherosclerosis.

In accordance with some embodiments, the patient has anemia. In accordance with some embodiments, the patient has anemia of a chronic disease. In accordance with some embodiments, the patient has iron refractory iron deficiency anemia (IRIDA).

In accordance with some embodiments, the patient has diabetes mellitus. In accordance with some embodiments, the patient has type II diabetes mellitus. In accordance with some embodiments, the patient has insulin-resistant diabetes mellitus.

In accordance with some embodiments, the patient has liver disease. In accordance with some embodiments, the patient has non-alcoholic steatohepatitis (NASH).

In accordance with some embodiments, the patient has osteoporosis. In accordance with some embodiments, the patient has depression. In accordance with some embodiments, the patient has asthma. In accordance with some embodiments, the patient has a neuroinflammatory disorder. In accordance with some embodiments, the patient has Alzheimer's disease. In accordance with some embodiments, the patient has Parkinson's disease. In accordance with some embodiments, the patient has multiple sclerosis. In accordance with some embodiments, the patient has amyotrophic lateral sclerosis (ALS).

In accordance with some embodiments, the patient has age-related macular degeneration (AMD).

In accordance with some embodiments, the patient has cancer. In some embodiments, the cancer is selected from the group consisting of solid tumors, small cell lung cancer, non-small cell lung cancer, hematologic malignancies, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), lymphomas , Hodgkin's lymphoma and liver adenoma.

In accordance with some embodiments, the patient has a skin disorder.

In accordance with some embodiments, the method prevents aging in a patient.

In yet another aspect, methods are provided herein for treating inflammation in a patient with cardiovascular disease. The methods include: administering an IL-6 antagonist to a patient with cardiovascular disease and a CRP level greater than 2 mg/L, at a dose that is sufficient to reduce CRP levels to 2 mg/L or less without causing neutropenia. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 30% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 20% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 10% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.

In yet another aspect, methods are provided herein for treating inflammation in a patient with chronic kidney disease (CKD). The methods include: administering an IL-6 antagonist to a patient with CKD and a CRP level greater than 2 mg/L, at a dose that is sufficient to reduce CRP levels to 2 mg/L or less without causing neutropenia.

In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 30% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 20% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is no more than 10% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist.

Brief description of drawings

These and other features, aspects and advantages of the present invention will be better understood in view of the following description and the accompanying drawings, in which:

in fig. 1 shows the dose escalation schedule for the randomized, double-blind, placebo-controlled phase 1/phase 2 trial of COR-001 in hemodialysis patients described in Example 1;

in fig. Figure 2 shows the time course and efficacy analysis for the treatment phase and the follow-up phase for the safety study;

in fig. 3A and 3B show C-reactive protein (CRP) assay results in responding patients following treatment with COR-001 (anti-IL-6 antibody) or canakinumab (anti-IL1aaa antibody). In fig. 3A shows the treatment response rate as measured by C-reactive protein levels following intravenous treatment with COR-001 in patients with stage 5 chronic kidney disease who were on dialysis in the clinical trial described in Example 1. The baseline hsCRP level was 12. 4 mg/l. A patient was defined as a responder when the mean hsCRP level was <2 mg/L at week 12. FIG. 3B shows the treatment response rate as measured by C-reactive protein levels following canakinumab treatment in the CANTOS trial as described in the scientific literature. The baseline hsCRP level was 5.5 mg/L. A patient was defined as a treatment responder when the hsCRP level was <2 mg/L at 3 months;

in fig. 4 shows the results of hemoglobin analysis in responding patients after treatment with COR-001 at doses of 2 mg, 6 mg and 20 mg. A patient was defined as responding to treatment when there was an increase in hemoglobin levels of 1 g/dL or more after Day 29. Investigators were not allowed to change the ESA dosage until Day 29 was reached;

in fig. Figure 5 shows the effect of COR-001 on the cardiac diastolic function parameter, NTproBNP;

in fig. 6A and 6B present the incidence of adverse treatment response in patients in terms of neutrophil and platelet counts. In fig. Figure 6A presents the incidence of adverse treatment response in patients as neutrophil counts. A patient was defined as having an unfavorable response when the mean neutrophil count was <2 x 10 ⁶ /ml at Week 12. FIG. Figure 6B presents the rate of adverse treatment response in patients as a platelet count. A patient was defined as having an unfavorable response when the mean platelet count was <100 x 10 ⁶ /mL at Week 12.

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Detailed Disclosure of the Invention

1. Definitions.

Unless otherwise defined, all technical and scientific terms used herein have the meaning that is commonly understood by one skilled in the art to which the present invention relates.

As used herein, interleukin 6 (IL-6) or IL-6 polypeptide refers to a polypeptide or fragment thereof having an amino acid sequence that is at least about 85% or more identical to the amino acid sequence reported in NCBI under accession number NP_000591 and having a biological IL-6 activity. IL-6 is a pleiotropic cytokine with numerous biological functions. Exemplary biological activities of IL-6 include immunostimulatory and proinflammatory activities. An exemplary amino acid sequence of IL-6 is presented below:

MCVGARRLGR GPCAALLLLG LGLSTVTGLH CVGDTYPSND RCCHECRPGN GMVSRCSRSQ

NTVCRPCGPG FYNDWSSKP CKPCTWCNLR SGSERKQLCT ATQDTVCRCR AGTQPLDSYK

121 PGVDCAPCPP GHFSPGDNQA CKPWTNCTLA GKHTLQPASN SSDAICEDRD PPATQPQETQ

181 GPPARPITVQ PTEAWPRTSQ GPSTRPVEVP GGRAVAAILG LGLVLGLLGP LAILLALYLL

241 RRDQRLPPDA HKPPGGGSFR TPIQEEQADA HSTLAKI (SEQ ID NO:1)

As used herein, interleukin 6 (IL-6) nucleic acid refers to a polynucleotide encoding an interleukin 6 (IL-6) polypeptide. An exemplary interleukin 6 (IL-6) nucleic acid sequence is provided under NCBI accession number NM_000600. An illustrative sequence under NCBI accession number NM_000600 is presented below:

AATATTAGAG TTSSAASSSS CAATAAATAT AGGACTGGAG ATGTCTGAGG CTCATTCTGC

CCTCGAGCCC ACCGGGAACG AAAGAGAAGC TSTATTSSS CTCCAGGAGC CCAGCTATGA

121 ASTCTTTTC CACAAGCGCC TTCGGTCCAG TTGCCTTCTC CCTGGGGCTG CTCCTGGTGT

181 TGCCTGCTGC CTTCCCTGCC CCAGTACCCC CAGGAGAAGA TTCCAAAGAT GTAGCCGCCC

241 CACACAGACA GCCACTCACC TCTTCAGAAC GAATTGACAA ACAAATTCGG TACATCCTCG

301 ACGGCATCTC AGCCCTGAGA AAGGAGACAT GTAACAAGAG TAACATGTGT GAAAGCAGCA

361 AAGAGGCACT GGCAGAAAAC AACCTGAACC TTCCAAAGAT GGCTGAAAAA GATGGATGCT

421 TCCAATCTGG ATTCAATGAG GAGACTTGCC TGGTGAAAAT CATCACTGGT CTTTTGGAGT

481 TTGAGGTATA CCTAGAGTAC CTCCAGAACA GATTTGAGAG TAGTGAGGAA CAAGCCAGAG

541 CTGTGCAGAT GAGTACAAAA GTCCTGATCC AGTTCCTGCA GAAAAAGGCA AAGAATCTAG

601 ATGCAATAAC CACCCCTGAC CCAASSASSAA ATGCCAGCCT GCTGACGAAG CTGCAGGCAC

661 AGAACCAGTG GCTGCAGGAC ATGACAACTC ATTSTSATTTST GCGCAGCTTT AAGGAGTTCC

721 TGCAGTCCAG CCTGAGGGCT CTTCGGCAAA TGTAGCATGG GCACCCAGA TTGTTGTTGT

781 TAATGGGCAT TSSTTTTTST GGTCAGAAAC CTGTCCACTG GGCACAGAAC TTATGTTGTT

841 CTCTATGGAG AACTAAAAGT ATGAGCGTTA GGACACTATT TTAATTTATTT TTAATTTTATT

901 AATATTTAAA TATGTGAAGC TGAGTTAATT TATGTAAGTC ATATTTTAAT TTTTAAGAAG

961 TACCACTTGA AASATTTTAT GTATTAGTTT TGAAATAATA ATGGAAAGTG GCTATGCAGT

1021 TTGAATATCC TTTGTTTCAG AGCCAGATCA TTTCTTGGAA AGTGTAGGCT TASSTSAAAT

1081 AAATGGCTAA STTATASATA TTTTTAAAGA AATATTTATA TTGTATTTAT ATAATGTATA

1141 AATGGTTTTTT ATASSAAATAA ATGGCATTTT AAAAAATTTSA GCAAAAAAAA AAAAAAAAAAA

1201 A (SEQ ID NO:2)

As used herein, the interleukin 6 receptor (IL-6R) complex refers to the protein complex containing the alpha subunit of the IL-6 receptor (IL-6Ra) and the interleukin 6 signal transduction glycoprotein 130 (gp130), also called the P subunit interleukin 6 receptor (IL-6Re). As used herein, an interleukin 6 receptor α-subunit polypeptide (IL-6Ra) refers to a polypeptide or fragment thereof having an amino acid sequence that is at least about 85% or more identical to the amino acid sequence reported in NCBI under accession number NP_000556 or NP_852004, and having the biological activity of the IL-6 receptor. Exemplary biological activities of IL-6Ra include binding to IL-6, binding to glycoprotein 130 (gp130), and regulation of cell growth and differentiation. An exemplary IL-6R sequence is shown below:

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MLAVGCALLA ALLAAPGAAL APRRCPAQEV ARGVLTSLPG DSVTLTCPGV EPEDNATVHW

VLRKPAAGSH PSRWAGMGRR LLLRSVQLHD SGNYSCYRAG RPAGTVHLLV DVPPEEPQLS

121 CFRKSPLSNV VCEWGPRSTP SLTTKAVLLV RKFQNSPAED FQEPCQYSQE SQKFSCQLAV 181 PEGDSSFYIV SMCVASSVGS KFSKTQTFQG CGILQPDPPA NITVTAVARN PRWLSVTWQD 241 PHSWNSSFYR LRFELRYRAE RSKTFTTWMV KDLQHHCVIH DAWSGLRHW QLRAQEEFGQ 301 GEWSEWSPEA MGTPWTESRS PPAENEVSTP MQALTTNKDD DNILFRDSAN ATSLPVQDSS 361 SVPLPTFLVA GGSLAFGTLL CIAIVLRFKK TWKLRALKEG KTSMHPPYSL GQLVPERPRP 421 TPVLVPLISP PVSPSSLGSD NTSSHNRPDA RDPR SPYDIS NTDYFFPR (SEQ ID NO:3)

As used herein, glycoprotein 130 (gp130) or interleukin 6 receptor β-subunit polypeptide (IL-6Re) refers to a polypeptide or fragment thereof with an amino acid sequence that is approximately 85% or more identical to the amino acid sequence submitted to NCBI under accession number NP_002175 , NP_786943 or NP_001177910, and having the biological activity of the IL-6 receptor. Exemplary biological activities of IL-6Re include binding to IL-6Ra, IL-6 receptor signaling activity, and regulation of cell growth, differentiation, hepcidin expression, etc. An exemplary IL-6RP sequence is shown below:

MLTLQTWLVQ ALFIFLTTES TGELLDPCGY ISPESPWQL HSNFTAVCVL KEKCMDYFHV

NANYIVWKTN HFTIPKEQYT IINRTASSVT FTDIASLNIQ LTCNILTFGQ LEQNVYGITI

121 ISGLPPEKPK NLSCIVNEGK KMRCEWDGGR ETHLETNFTL KSEWATHKFA DCKAKRDTPT

181 SCTVDYSTVY FVNIEVWVEA ENALGKVTSD HINFDPVYKV KPNPPHNLSV INSEELSSIL

241 KLTWTNPSIK SVIILKYNIQ YRTKDASTWS QIPPEDTAST RSSFTVQDLK PFTEYVFRIR

301 CMKEDGKGYW SDWSEEASGI TYEDRPSKAP SEWYKIDPSH TQGYRTVQLV WKTLPPFEAN

361 GKILDYEVTL TRWKSHLQNY TVNATKLTVN LTNDRYLATL TVRNLVGKSD AAVLTIPACD

421 FQATHPVMDL KAFPKDNMLW VEWTTPRESV KKYILEWCVL SDKAPCITDW QQEDGTVHRT

481 YLRGNLAESK CYLITVTPVY ADGPGSPESI KAYLKQAPPS KGPTVRTKKV GKNEAVLEWD

541 QLPVDVQNGF IRNYTIFYRT IIGNETAVNV DSSHTEYTLS SLTSDTLYMV RMAAYTDEGG

601 KDGPEFTFTT PKFAQGEIEA IWPVCLAFL LTTLLGVLFC FNKRDLIKKH IWPNVPDPSK

661 SHIAQWSPHT PPRHNFNSKD QMYSDGNFTD VSWEIEAND KKPFPEDLKS LDLFKKEKIN

721 TEGHSSGIGG SSCMSSSRPS ISSSDENESS QNTSSTVQYS TWHSGYRHQ VPSVQVFSRS

781 ESTQPLLDSE ERPEDLQLVD HVDGGDGILP RQQYFKQNCS QHESSPDISH FERSKQVSSV

841 NEEDFVRLKQ QISDHISQSC GSGQMKMFQE VSAADAFGPG TEGQVERFET VGMEAATDEG

901 MPKSYLPQTV RQGGYMPQ (SEQ ID NO:4)

Unless otherwise specified, an IL-6 antagonist refers to an agent that is capable of reducing the biological activity of IL-6. IL-6 antagonists include agents that reduce serum levels of IL-6 polypeptide, including agents that decrease the expression of IL-6 polypeptide or nucleic acid; agents that reduce the ability of IL-6 to bind to IL-6R; agents that reduce IL-6R expression; and agents that reduce signaling involving the IL-6R receptor when IL-6 binds to it. In accordance with preferred embodiments, the IL-6 antagonist reduces the biological activity of IL-6 by at least about 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%. As further described below, IL-6 antagonists include IL-6 binding polypeptides such as anti-IL-6 antibodies and antigen binding fragments or derivatives thereof; IL-6R binding polypeptides such as anti-IL-6R antibodies and antigen binding fragments or derivatives thereof; and synthetic chemical molecules such as JAK1 and JAK3 inhibitors.

The terms anti-IL-6 antibody or anti-IL-6 antibody refer to an antibody that specifically binds to IL-6. Antibodies to IL-6 include monoclonal and polyclonal antibodies that are specific for IL-6, as well as antigen-binding fragments or derivatives thereof. Antibodies to IL-6 are described in more detail below.

As used herein, the terms IL-6-mediated inflammation or IL-6-mediated inflammatory disorder refer to inflammation or inflammation-related disorder that IL-6 is known or suspected to contribute to the etiology or symptoms of inflammation.

The terms C-reactive protein or CRP refer to a polypeptide or fragment thereof having an amino acid sequence that is at least about 85% or more identical to the amino acid sequence reported in NCBI under accession number NP_000558 and having complement-activating activity. CRP levels increase in response to inflammation and can be measured using the hsCRP test (high sensitivity C-reactive protein test). An exemplary CRP sequence is presented below:

MEKLLCFLVL TSLSHAFGQT DMSRKAFVFP KESDTSYVSL KAPLTKPLKA FTVCLHFYTE

LSSTRGYSIF SYATKRQDNE ILIFWSKDIG YSFTVGGSEI LFEVPEVTVA PVHICTSWES

121 ASGIVEFWVD GKPRVRKSLK KGYTVGAEAS IILGQEQDSF GGNFEGSQSL VGDIGNVNMW

181 DFVLSPDEIN TIYLGGPFSP NVLNWRALKY EVQGEVFTKP QLWP (SEQ ID NO:5)

As used herein, hepcidin refers to a polypeptide with an amino acid sequence that is at least about 85% or more identical to the amino acid sequence reported in NCBI under accession number NP_066998 (hepcidin pre-protein), or a biologically active fragment thereof. Exemplary biological activities of hepcidin include binding to and reducing levels of the iron export channel ferroportin, inhibition of iron transport, inhibition of intestinal iron uptake, and inhibition of iron release from macrophages and the liver. An exemplary amino acid sequence of the hepcidin preprotein is presented below:

MALSSQIWAA CLLLLLLLAS LTSGSVFPQQ TGQLAELQPQ DRAGARASWM PMFQRRRRRD

THFPICIFCC GCCHRSKCGM SSKT (SEQ ID NO:6)

Regarding the above sequence, hepcidin exists in various forms, including preprohormone (amino acids 25-84), prohormone (amino acids 25-84) and mature forms called hepcidin-25 (amino acids 60-84), hepcidin-22 ( amino acids 63-84) and hepcidin20 (amino acids 65-84).

A hepcidin-mediated disorder is any disorder in which hepcidin expression contributes to the etiology of the disorder or any of its symptoms.

The terms immunosuppression or immune suppression refer to a decrease in the activation or effectiveness of the immune system. Immunosuppression can be measured by the number of white blood cells, such as neutrophils.

As used herein, a neutrophil or neutrocyte refers to a type of white blood cell that is an integral part of the innate immune system. Absolute neutrophil count (ANC) can be used in diagnosis and prognosis. Low numbers of neutrophils are called neutropenia.

The term agent refers to any compound or composition suitable for administration as part of a therapy and specifically includes chemical compounds; proteins, including antibodies or antigen-binding fragments thereof; peptides and nucleic acid molecules.

The term subject refers to a human or non-human mammal, including, but not limited to, cow, equine, dog, sheep, cat and rodent subjects, including mouse and rat subjects. A patient is a human subject in need of treatment.

As used herein, the terms treat, administer treatment, treat and the like refer to reducing or ameliorating a disorder and/or signs or symptoms associated with it, or slowing or stopping its progression. It will be understood that, although not excluded, treatment of a disorder or condition does not require that the disorder, condition, or symptoms associated therewith be completely eliminated.

As used herein, pre-treatment means prior to the first administration of an IL-6 antagonist according to the methods described herein. The term pre-treatment does not exclude, but often includes, the time before administration of treatment agents other than an IL-6 antagonist.

As used herein, the term post-treatment means after administration of an IL-6 antagonist according to the methods described herein. The term post-treatment includes the time following any administration of an IL-6 antagonist at any dosage described herein. The term post-treatment also includes the time following the IL-6 antagonist treatment phase.

In this disclosure, contains, contains, which contains, has, includes, including, and their linguistic variations have the meaning ascribed to them under US patent law, allowing for the presence of additional components beyond those expressly listed.

The term biological sample refers to any tissue, cell, fluid or other material obtained from an organism (eg, a human subject). In certain embodiments, the biological sample is serum or blood.

Unless otherwise specified, the numbering of residues in the antibody constant region corresponds to the amino acid numbering of the EU antibody as described by Kabat.

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2. Methods for treating IL-6-mediated inflammation.

In accordance with the first aspect, methods of treating IL-6-mediated inflammation in a patient are provided. The methods involve administering an IL-6 antagonist to a patient with IL-6-mediated inflammation at a dose that is sufficient to reduce inflammation without causing immunosuppression.

2.1. Serum levels of CRP and IL-6 before treatment.

In the methods described herein, the patient has IL-6 mediated inflammation.

In typical embodiments, the patient has elevated CRP levels prior to treatment.

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 pre-treatment CRP levels of at least 7.5 mg/L, 10 mg/L, 12.5 mg/L, or 15 mg/L. In accordance with various embodiments, the patient has a pre-treatment CRP level of at least 2 mg/L. In accordance with various embodiments, the patient has a pre-treatment CRP level of at least 2.5 mg/L. In accordance with various embodiments, the patient has a pre-treatment CRP level of at least 5 mg/L. In accordance with various embodiments, the patient has a pre-treatment CRP level of at least 7.5 mg/L. In accordance with various embodiments, the patient has a pre-treatment CRP level of at least 10 mg/L. In accordance with various embodiments, the patient has a pre-treatment CRP level of at least 12.5 mg/L. In accordance with various embodiments, the patient has a pre-treatment CRP level of at least 15 mg/L.

In accordance with some embodiments of the methods described herein, the patient has elevated serum IL-6 levels prior to treatment. In some embodiments, the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml. In accordance with 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, according at least 12 pg/ml, at least 13 pg/ml, at least 14 pg/ml or at least 15 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 2.5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 7.5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 12.5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL6 level of at least 15 pg/ml.

In accordance with some embodiments, the patient has elevated pre-treatment serum levels of CRP and elevated pre-treatment levels of IL-6. In certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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.

2.2. Decreased levels of IL-6 and C-reactive protein (CRP).

In typical embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce free IL-6 serum levels in the patient below pre-treatment levels.

In some embodiments, the level of free IL-6 in the serum is reduced by at least 10% compared to pre-treatment levels. In accordance with various embodiments, the serum level of free IL-6 is reduced by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to pre-treatment levels. In accordance with certain embodiments, the level of free IL-6 in the serum is reduced by at least 20% compared to pre-treatment levels. In accordance with certain embodiments, the level of free IL-6 in the serum is reduced by at least 30% compared to pre-treatment levels. In accordance with certain embodiments, the level of free IL-6 in the serum is reduced by at least 40% compared to pre-treatment levels. In accordance with certain embodiments, the level of free IL-6 in the serum is reduced by at least 50% compared to pre-treatment levels. In accordance with certain embodiments, the level of free IL-6 in the serum is reduced by at least 60% compared to pre-treatment levels. In accordance with certain embodiments, the level of free IL-6 in the serum is reduced by at least 70% compared to pre-treatment levels. In accordance with certain embodiments, the level of free IL-6 in the serum is reduced by at least 80% compared to pre-treatment levels. In accordance with certain embodiments, the level of free IL-6 in the serum is reduced by at least 90% compared to pre-treatment levels.

In some embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce CRP levels in the patient below pre-treatment levels. In some embodiments, IL-6-mediated inflammation is measured by CRP levels.

In certain embodiments, the post-treatment CRP level is no more than 5 mg/L. In certain embodiments, the post-treatment CRP level is no more than 2.5 mg/L. In certain embodiments, the post-treatment CRP level is no more than 2 mg/L. In certain embodiments, the post-treatment CRP level is no more than 1 mg/L. In some embodiments, the CRP level is reduced by at least 10% compared to pre-treatment levels. In accordance with various embodiments, the CRP level is reduced by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to pre-treatment levels. In accordance with certain embodiments, the CRP level is reduced by at least 20% compared to pre-treatment levels. In accordance with certain embodiments, the CRP level is reduced by at least 30% compared to pre-treatment levels. In accordance with certain embodiments, the CRP level is reduced by at least 40% compared to pre-treatment levels. In accordance with certain embodiments, the CRP level is reduced by at least 50% compared to pre-treatment levels. In accordance with certain embodiments, the CRP level is reduced by at least 60% compared to pre-treatment levels. In accordance with certain embodiments, the CRP level is reduced by at least 70% compared to pre-treatment levels. In certain embodiments, the CRP level is reduced by at least 80% compared to pre-treatment levels. In accordance with certain embodiments, the CRP level is reduced by at least 90% compared to pre-treatment levels.

2.3. Neutrophil level.

2.3.1. Absolute neutrophil count (ANC).

In the methods described herein, the IL-6 antagonist is administered at a dose sufficient to reduce inflammation without causing immunosuppression. In some embodiments, immunosuppression in a patient is measured by absolute neutrophil count (ANC).

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 certain embodiments, the post-treatment ANC is at least 500 cells/μl. In certain embodiments, the post-treatment ANC is at least 750 cells/μl. In certain embodiments, the post-treatment ANC is at least 1000 cells/μl. In certain embodiments, the post-treatment ANC is at least 1250 cells/μl. In certain embodiments, the post-treatment ANC is at least 1500 cells/μl. In certain embodiments, the post-treatment ANC is at least 1750 cells/μl. In certain embodiments, the post-treatment ANC is at least 2000 cells/μl.

In some embodiments, the ANC is reduced by no more than 2500 cells/μL compared to pre-treatment levels. In various embodiments, the ANC is reduced by no more than 2000 cells/μL, 1900 cells/μL, 1800 cells/μL, 1700 cells/μL, 1600 cells/μL, 1500 cells/μL, 1400 cells/μL, 1300 cells/μL 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 compared with pre-treatment levels. In certain embodiments, the ANC is reduced by no more than 2000 cells/μL compared to pre-treatment levels. In certain embodiments, the ANC is reduced by no more than 1750 cells/μL compared to pre-treatment levels. In certain embodiments, the ANC is reduced by no more than 1500 cells/μL compared to pre-treatment levels. In certain embodiments, the ANC is reduced by no more than 1250 cells/μL compared to pre-treatment levels. In certain embodiments, the ANC is reduced by no more than 1000 cells/μL compared to pre-treatment levels. In certain embodiments, the ANC is reduced by no more than 750 cells/μL compared to pre-treatment levels. In certain embodiments, the ANC is reduced by no more than 500 cells/μL compared to pre-treatment levels.

In some embodiments, ANC is reduced by no more than 70% compared to pre-treatment levels. In various embodiments, the ANC is reduced by no more than 60%, 50%, 40%, 30%, 20%, 10%, or 5% compared to pre-treatment levels. In certain embodiments, ANC is reduced by no more than 60% compared to pre-treatment levels. In certain embodiments, ANC is reduced by no more than 50% compared to pre-treatment levels. In certain embodiments, ANC is reduced by no more than 40% compared to pre-treatment levels. In certain embodiments, ANC is reduced by no more than 30% compared to pre-treatment levels. In certain embodiments, ANC is reduced by no more than 20% compared to pre-treatment levels. In certain embodiments, ANC is reduced by no more than 10% compared to pre-treatment levels. In certain embodiments, ANC is reduced by no more than 5% compared to pre-treatment levels. In some embodiments, ANC is not reduced from pre-treatment levels.

2.4. Lipoprotein(a) level.

In some embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce lipoprotein(a) levels in the patient below pretreatment levels.

In some embodiments, lipoprotein(a) levels are reduced by at least 10% compared to pre-treatment levels. In accordance with various embodiments, the lipoprotein(a) level is reduced by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to pre-treatment levels. In accordance with certain embodiments, the lipoprotein(a) level is reduced by at least 20% compared to pre-treatment levels. In certain embodiments, lipoprotein(a) levels are reduced by at least 30% compared to pre-treatment levels. In certain embodiments, lipoprotein(a) levels are reduced by at least 40% compared to pre-treatment levels. In accordance with certain embodiments, the lipoprotein(a) level is reduced by at least 50% compared to pre-treatment levels. In certain embodiments, lipoprotein(a) levels are reduced by at least 60% compared to pre-treatment levels. In certain embodiments, lipoprotein(a) levels are reduced by at least 70% compared to pre-treatment levels. In accordance with certain embodiments, lipoprotein(a) levels are reduced by at least 80% compared to pre-treatment levels. In accordance with certain embodiments, the lipoprotein(a) level is reduced by at least 90% compared to pre-treatment levels.

2.5. LDL level.

In accordance with some embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce lipoprotein(a) levels in a patient without significantly increasing low-density lipoprotein (LDL) levels in the patient. In some embodiments, the LDL level is increased by no more than 15% compared to pre-treatment levels. In various embodiments, the LDL level is increased by no more than 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, or 1% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 12% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 10% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 8% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 6% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 5% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 4% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 3% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 2% compared to pre-treatment levels. In certain embodiments, the LDL level is increased by no more than 1% compared to pre-treatment levels.

In accordance with certain embodiments, the LDL level is not increased compared to pre-treatment levels.

2.6. IL-6-mediated inflammatory disorders.

In the methods described herein, the patient has an IL-6 mediated inflammatory disorder.

2.6.1. Non-hepcidin-mediated inflammatory disorders.

In accordance with various embodiments, the IL-6-mediated inflammatory disorder is not a hepcidin-mediated disorder. Hepcidin-mediated disorders are described in US Patent Application No. US 2017/0029499, the disclosure of which is incorporated herein by reference in its entirety.

2.6.2. Hepcidin-mediated inflammatory disorders.

In accordance with various embodiments, the IL-6-mediated inflammatory disorder is a hepcidin-mediated disorder. Hepcidin-mediated disorders are described in US Patent Application No. US 2017/0029499, the disclosure of which is incorporated herein by reference in its entirety. In certain embodiments, the patient has a hepcidin-mediated disorder and at least one copy of the major allele at SNP rs855791 of TMPRSS6 (amino acid 736A). In other embodiments, the patient has a hepcidin-mediated disorder and is homozygous for the minor allele at SNP rs855791 of TMPRSS6 (amino acid 736V). In certain embodiments, the patient has a hepcidin-mediated disorder and an unknown genotype at the rs855791 TMPRSS6 SNP.

2.6.3. Non-autoimmune inflammatory disorder.

In accordance with various embodiments, the IL-6 mediated inflammatory disorder is a non-autoimmune IL-6 mediated inflammatory disorder. In certain 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.

2.6.4. Kidney disease.

In accordance with various embodiments, the patient has kidney disease. In accordance with some embodiments, the kidney disease is chronic kidney disease (CKD).

In some embodiments, the patient has KDOQI stages 1-5 chronic kidney disease. In some embodiments, the patient has KDOQI stage 3-5 chronic kidney disease. In co

- 14 045389 in accordance with 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 stages according to the KDOQI classification. In certain embodiments, the patient has stage 5 chronic kidney disease according to the KDOQI classification.

In accordance with some embodiments, the patient is on dialysis. In accordance with some embodiments, the patient is not on dialysis. In a certain embodiment, the patient has KDOQI stage 3-5 chronic kidney disease and the patient is not on dialysis. In a certain embodiment, the patient has KDOQI stage 5 chronic kidney disease and the patient is on dialysis.

In accordance with some embodiments, the patient has cardiorenal syndrome (CRS). In accordance with certain embodiments, the patient has CRS type 4.

In accordance with some embodiments, the patient received dialysis treatment.

2.6.5. Cardiovascular disease.

According to various embodiments, the patient has cardiovascular disease.

In accordance with some embodiments, the patient has suffered a myocardial infarction. In certain embodiments, the patient has suffered a myocardial infarction and has a CRP level of 2 mg/L or more. In certain embodiments, the patient suffered a myocardial infarction within 60 days prior to the first administration of the IL-6 antagonist. In certain embodiments, the patient suffered a myocardial infarction within 30 days, 14 days, 7 days, 48 hours, or 24 hours prior to the first administration of the IL-6 antagonist. In accordance with some embodiments, the patient has atherosclerosis but has not had a myocardial infarction. In certain embodiments, the patient has atherosclerosis but has not had a myocardial infarction and has a CRP level of 2 mg/L or greater.

In accordance with some embodiments, the cardiovascular disease is congestive heart failure (CHF). In accordance with certain embodiments, the patient has congestive heart failure (CHF) with reduced ejection fraction. In certain embodiments, the patient has congestive heart failure (CHF) with intermediate ejection fraction. In accordance with certain embodiments, the patient has congestive heart failure (CHF) with preserved ejection fraction.

In accordance with various embodiments, the IL-6-mediated inflammatory disorder is heart failure that is not diuretic-resistant. Diuretic-resistant heart failure is described in international application WO 2018/144773, the disclosure of which is incorporated herein by reference in its entirety.

In accordance with some embodiments, the cardiovascular disease is diuretic-resistant heart failure. Diuretic-resistant heart failure is described in international application WO 2018/144773, the disclosure of which is incorporated herein by reference in its entirety.

In accordance with some embodiments, the cardiovascular disease is an acute coronary syndrome.

In certain embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce non-fatal myocardial infarction, non-fatal stroke, and/or death due to cardiovascular disease. 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 improve cardiac function. In some embodiments, the IL-6 antagonist is administered at a dose sufficient to reduce fibrosis following acute myocardial infarction.

2.6.6. Anemia.

In accordance with various embodiments, the patient has anemia. In accordance with some embodiments, the patient has anemia of a chronic disease. In accordance with some embodiments, the patient has iron refractory iron deficiency anemia (IRIDA). In accordance with some of these embodiments, the patient has received treatment with an erythropoiesis stimulating agent (ESA). In accordance with some embodiments, the patient received treatment with iron supplements. In accordance with some embodiments, the patient has received treatment with a blood or red blood cell transfusion.

In accordance with some embodiments, the IL-6 antagonist is administered at a dose sufficient to reverse the development of functional iron deficiency.

- 15 045389

2.6.7. Diabetes.

In accordance with some embodiments, the patient has diabetes mellitus. In accordance with certain embodiments, the patient has type II diabetes. In accordance with certain embodiments, the patient has insulin-resistant diabetes mellitus.

2.6.8. Liver disease.

In accordance with some embodiments, the patient has liver disease. In accordance with certain embodiments, the patient has non-alcoholic steatohepatitis (NASH).

2.6.9. Osteoporosis.

In accordance with some embodiments, the patient has osteoporosis.

2.6.10. Depression.

In accordance with some embodiments, the patient has depression.

2.6.11. Asthma.

In accordance with some embodiments, the patient has asthma.

2.6.12. Neuroinflammatory disorder.

In accordance with some embodiments, the patient has a neuroinflammatory disorder. In accordance with certain embodiments, the patient has Alzheimer's disease. In accordance with certain embodiments, the patient has Parkinson's disease. In accordance with certain embodiments, the patient has multiple sclerosis. In accordance with certain embodiments, the patient has amyotrophic lateral sclerosis (ALS).

2.6.13. Age-related macular degeneration.

In accordance with some embodiments, the patient has age-related macular degeneration (AMD).

2.6.14. Malignant tumor.

In accordance with various embodiments, the patient has cancer. In some embodiments, the cancer is selected from the group consisting of solid tumors, small cell lung cancer, non-small cell lung cancer, hematologic malignancies, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), lymphomas, and Hodgkin lymphoma.

2.6.15. Skin disease.

According to various embodiments, the patient has a skin disease such as atopic dermatitis or psoriasis.

2.6.16. Aging.

In accordance with some embodiments, the method prevents aging in a patient.

2.7. IL-6 antagonists.

An IL-6 antagonist used in the methods described herein is capable of reducing the biological activity of IL-6.

2.7.1. Antibodies to IL-6.

In accordance with various embodiments, the IL-6 antagonist is an anti-IL-6 antibody or an antigen-binding fragment or derivative thereof.

In typical embodiments, the anti-IL-6 antibody neutralizes the biological activity of IL-6. In accordance with some embodiments, the neutralizing antibody prevents IL-6 from binding to the IL-6 receptor.

In accordance with some embodiments, the IL-6 antagonist is an anti-IL-6 monoclonal antibody. In accordance with some embodiments, the IL-6 antagonist is a polyclonal composition comprising a plurality of anti-IL-6 antibody species, each of the plurality of antibodies having unique CDRs.

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

In accordance with some embodiments, the anti-IL-6 antibody comprises a backbone. In certain embodiments, the backbone is an Fc, optionally a human Fc. In accordance with some embodiments, the anti-IL-6 antibody comprises a heavy chain constant region from a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, the anti-IL-6 antibody comprises a heavy chain constant region from the IgG class and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

In accordance with some embodiments, the IL-6 antagonist is an immunoconjugate or fusion protein comprising an IL-6 antigen-binding moiety.

In some embodiments, the antibody is bispecific or multispecific, wherein at least one of the antigen binding portions is specific for IL-6. In accordance with some embodiments, the antibody is fully human. In accordance with some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric and has non-human V regions and human C region domains. In accordance with some embodiments, the antibody is murine.

In typical embodiments, the anti-IL-6 antibody has a K _D for binding to human IL-6 of less than 100 nM. In some embodiments, the anti-IL-6 antibody has a K _D for binding to human IL-6 of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nM. In certain embodiments, the anti-IL-6 antibody has a Kd for binding to human IL-6 of less than 5 nM, 4 nM, 3 nM, or 2 nM. In selected embodiments, the anti-IL-6 antibody has a K _D for binding to human IL-6 of less than 1 nM, 750 pM, or 500 pM. In certain embodiments, the anti-IL-6 antibody has a K _D for binding to human IL-6 of no more than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM.

In typical embodiments, the anti-IL-6 antibody has a half-life after intravenous administration of at least 7 days. In certain embodiments, the anti-IL-6 antibody has a half-life of at least 14 days, at least 21 days, or at least 30 days.

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

In certain embodiments, the IgG constant domain comprises substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is a substitution for tyrosine, the amino acid substitution at amino acid residue 254 is a substitution for threonine, and the amino acid substitution at amino acid residue 256 is a glutamic acid replacement (YTE). See US Pat. No. 7,083,784, which is incorporated herein by reference in its entirety. In certain extended half-life embodiments, the IgG constant domain contains 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: 17591769 (2006)).

In some embodiments, the half-life of an anti-IL-6 antibody is increased by taking advantage of the FcRN binding properties of human serum albumin. In certain embodiments, 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 bacterial albumin-binding domains (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 for IL-6 and the other specificity being for human serum albumin (Ablynx, WO 2006/122825 (bispecific nanobody)).

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

2.7.1.1. COR-001 and derivatives.

In certain preferred embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of COR-001. Antibody COR-001 (also known as MEDI5117) is described in International Application WO2010/088444 and US Patent Application No. US2012/0034212, the disclosures of which are incorporated herein by reference in their entirety. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of COR-001. In certain embodiments, the antibody is a full-length COR-001 antibody. Antibody COR-001 has the following CDR and heavy and light chain sequences:

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CDR1 VH COR-001

SNYMI (SEQ ID NO:7)

CDR2 VH COR-001

DLYYYAGDTYYADSVKG (SEQ ID NO:8)

CDR3 VH COR-001

WADDHPPWIDL (SEQ ID NO:9)

CDR1 VL COR-001

RASQGISSWLA (SEQ ID NO:10)

CDR2 VL COR-001

KASTLES (SEQ ID NO:11)

CDR3 VL COR-001

QQSWLGGS (SEQ ID NO:12)

Heavy chain COR-001

EVQLVESGGGLVQPGGSLRLSCAASGFTISSNYMIWVRQAPGKGLEWVSDLYYYAGDTYY

ADSVKGRFTMSRDISKNTVYLQMNSLRAEDTAVYYCARWADDHPPWIDLWGRGTLVTVSS

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:13)

Light chain COR-001

DIQMTQSPSTLSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKVLIYKASTLESGVPS

RFSGSGSGTEFTLTISSLQPDDFATYYCQQSWLGGSFGQGTKLEIKRTVAAPSVFIFPPS DEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:14)

In accordance with various embodiments, the anti-IL-6 antibody is a derivative of COR-001.

In accordance with some embodiments, the COR-001 derivative includes one or more amino acid substitutions in the V regions of the COR-001 heavy and/or light chain.

In certain embodiments, the COR-001 derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, less than 2 amino acid substitutions or 1 amino acid substitution compared to the original VH and/or VL of the anti-IL-6 antibody COR-001 while maintaining specificity for human IL-6.

In accordance with certain embodiments, the COR-001 derivative 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%,

- 18 045389 at least 95% or at least 99% identical amino acid sequence

VH and V _L domain of COR-001. Percent sequence identity was determined using BLAST algorithms using default parameters.

In accordance with certain embodiments, the COR-001 derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60% , at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the amino acid sequence of the corresponding CDRs of COR-001. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR VH and/or _VL derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically bind to human IL- 6).

2.7.1.2. Siltuximab and derivatives.

In certain embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of siltuximab. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of siltuximab. In certain embodiments, the antibody is a full-length siltuximab antibody.

In accordance with various embodiments, the anti-IL-6 antibody is a siltuximab derivative.

In accordance with some embodiments, the siltuximab derivative includes one or more amino acid substitutions in the V regions of the heavy and/or light chain of siltuximab.

In certain embodiments, the siltuximab derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions , less than 2 amino acid substitutions or 1 amino acid substitution compared to the original V _H and/or V _L of the anti-IL-6 antibody siltuximab while maintaining specificity for human IL-6. In accordance with certain embodiments, the siltuximab derivative 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 amino acid sequence VH and VL domain of siltuximab. Percent sequence identity was determined using BLAST algorithms using default parameters. In accordance with certain embodiments, the siltuximab derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, according to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least at least 99% identical to the amino acid sequence of the corresponding CDRs of siltuximab. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR VH and/or _VL derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically bind to human IL- 6).

2.7.1.3. Gerilimzumab and derivatives.

In certain embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of gerilimzumab. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of gerilimzumab. In certain embodiments, the antibody is a full-length gerilimzumab antibody.

In accordance with various embodiments, the anti-IL-6 antibody is a gerilimzumab derivative.

In accordance with some embodiments, the gerilimzumab derivative includes one or more amino acid substitutions in the V regions of the gerilimzumab heavy and/or light chain.

In certain embodiments, the gerilimzumab derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions , less than 2 amino acid substitutions or 1 amino acid substitution compared to the original VH and/or V _L of the anti-IL-6 antibody gerilimzumab while maintaining specificity for human IL-6. In certain embodiments, the gerilimzumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical amino acid sequence VH and V _L domains of gerilimzumab. Percent sequence identity was determined using BLAST algorithms using default parameters. In accordance with certain embodiments, the gerilimzumab derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, according to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least at least 99% identical to the amino acid sequence of the corresponding CDRs of gerilimzumab. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR VH and/or _VL derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically bind to human IL- 6).

2.7.1.4. Sirukumab and derivatives.

In certain embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of sirukumab. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of sirukumab. In certain embodiments, the antibody is a full-length sirukumab antibody.

In accordance with various embodiments, the anti-IL-6 antibody is a derivative of sirukumab.

In accordance with some embodiments, the sirukumab derivative includes one or more amino acid substitutions in the V regions of the sirukumab heavy and/or light chain.

In certain embodiments, the sirukumab derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions , less than 2 amino acid substitutions or 1 amino acid substitution compared to the original VH and/or VL of the anti-IL-6 antibody sirukumab while maintaining specificity for human IL-6.

In accordance with certain embodiments, the sirukumab derivative 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 amino acid sequence V _H and V _L domain of sirukumab. Percent sequence identity was determined using BLAST algorithms using default parameters. In accordance with certain embodiments, the sirukumab derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, according to at least by

65%, at least 70%, at least 75%, at least 80%, at least by

85%, at least 90%, at least 95%, or at least 99% identical in amino acid sequence to the corresponding sirukumab CDRs. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR V _H and/or V _L derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically bind to human IL -6).

2.7.1.5. Clazakizumab and derivatives.

In certain embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of clazakizumab. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of clazakizumab. In certain embodiments, the antibody is a full-length clazakizumab antibody.

In accordance with various embodiments, the anti-IL-6 antibody is a derivative of clazakizumab.

- 20 045389

In accordance with some embodiments, the clazakizumab derivative includes one or more amino acid substitutions in the V regions of the clazakizumab heavy and/or light chain.

In certain embodiments, the clazakizumab derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions , less than 2 amino acid substitutions or 1 amino acid substitution compared to the original VH and/or VL of the anti-IL-6 antibody clazakizumab while maintaining specificity for human IL-6.

In certain embodiments, the clazakizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical amino acid sequence V _H and V _L domain of clazakizumab. Percent sequence identity was determined using BLAST algorithms using default parameters. In accordance with certain embodiments, the clazakizumab derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, according to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least at least 99% identical to the amino acid sequence of the corresponding CDRs of clazakizumab. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR VH and/or VL derivatives contain conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically bind to human IL-6 ).

2.7.1.6. Olokizumab and derivatives.

In certain embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of olokizumab. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of olokizumab. In certain embodiments, the antibody is a full-length olokizumab antibody.

In accordance with various embodiments, the anti-IL-6 antibody is a derivative of olokizumab.

In accordance with some embodiments, the olokizumab derivative includes one or more amino acid substitutions in the V regions of the olokizumab heavy and/or light chain.

In certain embodiments, the olokizumab derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions , less than 2 amino acid substitutions or 1 amino acid substitution compared to the original V _H and/or V _L of the anti-IL-6 antibody olokizumab while maintaining specificity for human IL-6.

In accordance with certain embodiments, the olokizumab derivative 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 amino acid sequence V _H and V _L domain of olokizumab. Percent sequence identity was determined using BLAST algorithms using default parameters. In accordance with certain embodiments, the olokizumab derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, according to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least at least 99% identical to the amino acid sequence of the corresponding CDRs of olokizumab. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR VH and/or VL derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically bind to human IL-6 ).

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2.7.1.7. Other anti-IL-6 antibodies and derivatives.

In certain embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of an antibody selected from the group consisting of VX30 (VOPR003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of an antibody selected from the group consisting of VX30 (VOP-R003; Vaccinex), EB-007 (EBI029; Eleven Bio), and FM101. In certain embodiments, 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. In various embodiments, the anti-IL-6 antibody is a derivative of an antibody selected from the group consisting of VX30 (VOPR003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101.

2.7.2. Antibodies to the IL-6 receptor.

In various embodiments, the IL-6 antagonist is an anti-IL-6 receptor antibody (anti-IL-6R antibody) or an antigen-binding fragment or derivative thereof.

In accordance with typical embodiments, an anti-IL-6R antibody reduces the biological activity of the IL-6 receptor.

In accordance with some embodiments, the IL-6 antagonist is an anti-IL-6R monoclonal antibody. In accordance with some embodiments, the IL6 antagonist is a polyclonal composition comprising a plurality of anti-IL-6R antibody species, each of the plurality of antibodies having unique CDRs.

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

In accordance with some embodiments, the anti-IL-6R antibody comprises a backbone. In certain embodiments, the backbone is an Fc, optionally a human Fc. In accordance with some embodiments, the anti-IL-6R antibody comprises a heavy chain constant region from a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, the anti-IL-6R antibody comprises a heavy chain constant region from the IgG class and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

In accordance with some embodiments, the IL-6 antagonist is an immunoconjugate or fusion protein comprising an IL-6R antigen-binding moiety.

In accordance with some embodiments, the antibody is bispecific or multispecific, wherein at least one of the antigen binding portions has specificity for the IL-6 receptor.

In accordance with some embodiments, the antibody is fully human. In accordance with some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric and has non-human V regions and human C region domains. In accordance with some embodiments, the antibody is murine.

In typical embodiments, the anti-IL-6R antibody has a KD for binding to the human IL-6 receptor of less than 100 nM. In some embodiments, the anti-IL-6R antibody has a KD for binding to the human IL-6 receptor of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nM. In certain embodiments, the anti-IL-6R antibody has a KD for binding to the human IL-6 receptor of less than 5 nM, 4 nM, 3 nM, or 2 nM. In selected embodiments, the anti-IL-6R antibody has a KD for binding to the human IL-6 receptor of less than 1 nM, 750 pM, or 500 pM. In certain embodiments, the anti-IL-6R antibody has a KD for binding to the human IL-6 receptor of no more than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM. In typical embodiments, the anti-IL-6R antibody has a half-life after intravenous administration of at least 7 days. In certain embodiments, the anti-IL-6R antibody has a half-life of at least 14 days, at least 21 days, or at least 30 days.

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

In certain embodiments, the IgG constant domain comprises substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is a substitution for tyrosine, the amino acid substitution at amino acid residue 254 is a substitution for threonine, and the amino acid substitution at amino acid residue 256 is a glutamic acid replacement (YTE). See US Pat. No. 7,083,784, which is incorporated herein by reference in its entirety. In accordance with certain embodiments with

- 22 045389 with an extended half-life, the IgG constant domain contains 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: 17591769(2006)).

In some embodiments, the half-life of an anti-IL-6R antibody is increased by taking advantage of the FcRN binding properties of human serum albumin. In certain embodiments, the antibody is conjugated to albumin (Smith et al., Bioconjug. Chem., 12: 750-756 (2001)). In some embodiments, an anti-IL-6R antibody is fused to bacterial albumin-binding domains (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 for the IL-6 receptor and the other specificity for human serum albumin (Ablynx, WO 2006/122825 (bispecific nanobody)).

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

2.7.2.1. Tocilizumab and derivatives.

In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of tocilizumab. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of tocilizumab. In certain embodiments, the antibody is a full-length tocilizumab antibody.

In accordance with various embodiments, the anti-IL-6R antibody is a tocilizumab derivative.

In accordance with some embodiments, the tocilizumab derivative includes one or more amino acid substitutions in the V regions of the tocilizumab heavy and/or light chain.

In certain embodiments, the tocilizumab derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions , less than 2 amino acid substitutions or 1 amino acid substitution compared to the parent V _H and/or V _L of the anti-IL-6R antibody tocilizumab while maintaining specificity for the human IL-6 receptor. In certain embodiments, the tocilizumab derivative 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 amino acid sequence VH and VL domain of tocilizumab. Percent sequence identity was determined using BLAST algorithms using default parameters. In accordance with certain embodiments, the tocilizumab derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, according to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least at least 99% identical to the amino acid sequence of the corresponding CDRs of tocilizumab. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR VH and/or VL derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically bind to the human IL-1 receptor). 6). 2.7.2.2. Sarilumab and derivatives

In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of sarilumab. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of sarilumab. In certain embodiments, the antibody is a full-length sarilumab antibody.

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In accordance with various embodiments, the anti-IL-6R antibody is a sarilumab derivative.

In accordance with some embodiments, the sarilumab derivative includes one or more amino acid substitutions in the V regions of the sarilumab heavy and/or light chain.

In certain embodiments, the sarilumab derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions , less than 2 amino acid substitutions or 1 amino acid substitution compared to the original VH and/or V _L of the anti-IL-6R antibody sarilumab while maintaining specificity for the human IL-6 receptor.

In accordance with certain embodiments, the sarilumab derivative 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 amino acid sequence VH and VL domain of sarilumab. Percent sequence identity was determined using BLAST algorithms using default parameters. In accordance with certain embodiments, the sarilumab derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, according to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least at least 99% identical to the amino acid sequence of the corresponding CDRs of sarilumab. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR VH and/or VL derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically bind to the human IL-1 receptor). 6).

2.7.2.3. Vobarilizumab and derivatives.

In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of vobarilizumab. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a light chain V region of vobarilizumab. In certain embodiments, the antibody is a full-length vobarilizumab antibody.

In accordance with various embodiments, the anti-IL-6R antibody is a derivative of vobarilizumab.

In accordance with some embodiments, the vobarilizumab derivative includes one or more amino acid substitutions in the V regions of the vobarilizumab heavy and/or light chain.

In certain embodiments, the vobarilizumab derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions , less than 2 amino acid substitutions or 1 amino acid substitution compared to the original VH and/or VL of the anti-IL-6R antibody vobarilizumab while maintaining specificity for the human IL-6 receptor.

In certain embodiments, the vobarilizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical amino acid sequence V _H and V _L domain of vobarilizumab. Percent sequence identity was determined using BLAST algorithms using default parameters. In accordance with certain embodiments, the vobarilizumab derivative comprises an amino acid sequence, wherein the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, according to at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least at least 99% identical to the amino acid sequence of the corresponding CDRs of vobarilizumab. Percent sequence identity was determined using BLAST algorithms using default parameters.

In certain embodiments, the CDR V _H and/or V _L derivatives contain conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues that are not critical for the antibody to specifically binds to the human IL-6 receptor).

2.7.2.4. Other anti-IL-6R antibodies and derivatives.

In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of an antibody selected from the group consisting of SA237 (Roche), NI-1201 (NovImmune), and the antibody described in U.S. Patent Application Serial No. 2012 /0225060. In certain embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain V region and a 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 Application No. US 2012/0225060. In certain embodiments, the antibody is a full-length antibody selected from the group consisting of SA237 (Roche), NI-1201 (Novlmmune), and the antibody described in US patent application No. US 2012/0225060.

In accordance with various embodiments, the anti-IL-6R antibody is a derivative of an antibody selected from the group consisting of SA237 (Roche), NI-1201 (Novlmmune), or the antibody described in US patent application No. US 2012/0225060.

2.7.3. Antibodies to the IL-6:IL-6R complex.

In accordance with various embodiments, the IL-6 antagonist is an antibody specific for the complex of IL-6 and IL-6R. In accordance with certain embodiments, the antibody has six antibody CDRs selected from those described in US patent application No. US 2011/0002936, which is incorporated herein by reference in its entirety.

2.7.4. JAK and STAT inhibitors.

In accordance with various embodiments, the IL-6 antagonist is an inhibitor of the JAK signaling pathway. In accordance with some embodiments, the JAK inhibitor is a JAK1-specific inhibitor. In accordance with some embodiments, the JAK inhibitor is a JAK3-specific inhibitor. In accordance with some embodiments, the JAK inhibitor is a non-selective JAK inhibitor.

In certain embodiments, the JAK inhibitor is selected from the group consisting of tofacitinib (Xeljanz), decernotinib, ruxolitinib, upadacitinib, baricitinib, filgotinib, lestaurtinib, pacritinib, peficitinib, INCB-039110, ABT-494, INCB047986, and AC-410.

In accordance with various embodiments, the IL-6 antagonist is a STAT3 inhibitor. In a specific embodiment, the inhibitor is AZD9150 (AstraZeneca, Isis Pharmaceuticals), an antisense molecule for STAT3.

2.7.5. Additional IL-6 antagonists.

In accordance with various embodiments, the IL-6 antagonist is an antagonist peptide.

In certain embodiments, the IL-6 antagonist is C326 (IL-6 inhibitor from Avidia, also known as AMG220), or FE301, a recombinant IL-6 inhibitor protein (Ferring International Center S.A., Conaris Research Institute AG). In some embodiments, the anti-IL-6 antagonist comprises a soluble gp130, FE301 (Conaris/Ferring).

2.8. Pharmaceutical composition.

The IL-6 antagonist used in the methods described herein can be formulated in any suitable pharmaceutical composition for administration via any suitable route of administration. Suitable routes of administration include, but are not limited to, intravitreal, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary and subcutaneous routes.

The pharmaceutical composition may contain one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one skilled in the art will be able to select suitable pharmaceutical excipients. Accordingly, all pharmaceutical excipients presented below are intended to be illustrative and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety.

2.9. Dosing regimens.

The IL-6 antagonist is administered in a dose sufficient to reduce inflammation without causing immunosuppression.

2.9.1. Antibodies, antigen-binding fragments, peptides.

In typical embodiments, the anti-IL-6 antibody, antigen binding fragments, and IL-6 peptide antagonists are administered parenterally. In some parenteral embodiments, the IL-6 antagonist is administered intravenously. In certain intravenous embodiments, the IL-6 antagonist is administered as a bolus. In certain intravenous embodiments, the IL-6 antagonist is administered as an infusion. In certain intravenous embodiments, the IL-6 antagonist is administered as a bolus followed by infusion.

In some parenteral embodiments, the IL-6 antagonist is administered subcutaneously.

In various embodiments, the anti-IL-6 antibody, antigen-binding fragment, or IL-6 peptide antagonist is administered at a dose that is independent of the patient's weight or body surface area of the patient (constant dose). In some embodiments, the intravenous constant dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg or 1 mg. In some embodiments, the intravenous continuous dose is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the intravenous continuous dose is 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, the intravenous continuous dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the intravenous continuous dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the intravenous continuous dose is 200 mg, 300 mg, 400 mg, or 500 mg. In some embodiments, the intravenous constant dose is 0.1-1 mg, 1-10 mg, 10-15 mg, 15-20 mg, 20-30 mg, 30-40 mg, or 40-50 mg. In some embodiments, the intravenous continuous dose is 1-50 mg, 50-100 mg, or 100 mg-500 mg.

In some embodiments, the subcutaneous continuous dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg or 1 mg. In some embodiments, the subcutaneous continuous dose is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the subcutaneous continuous dose is 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, the subcutaneous continuous dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the subcutaneous continuous dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the subcutaneous continuous dose is 200 mg, 300 mg, 400 mg, or 500 mg. In some embodiments, the subcutaneous continuous dose is 0.1-1 mg, 1-10 mg, 10-15 mg, 15-20 mg, 20-30 mg, 3040 mg, or 40-50 mg. In some embodiments, the subcutaneous continuous dose is 1-50 mg, 50-100 mg, or 100 mg-500 mg.

In various embodiments, the anti-IL-6 antibody, antigen-binding fragment, or IL-6 peptide antagonist is administered as a dosage based on the patient's weight.

In some embodiments, the antagonist is administered at an intravenous dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0. 06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg or 0.1 mg/kg. In some embodiments, the antagonist is administered at an intravenous dose of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0. 6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, or 1.0 mg/kg. In some embodiments, the antagonist is administered at an intravenous dose of 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4 .5 mg/kg or 5 mg/kg.

In some embodiments, the antagonist is administered at a subcutaneous dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0. 06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg or 0.1 mg/kg. In some embodiments, the antagonist is administered at a subcutaneous dose of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0. 6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, or 1.0 mg/kg. In some embodiments, the antagonist is administered at a subcutaneous dose of 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4 .5 mg/kg or 5 mg/kg.

In various intravenous embodiments, the IL-6 antagonist is administered once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once a month. In various subcutaneous embodiments, the IL-6 antagonist is administered every 14 days, every 28 days, once a month, every two months (every two months), or every three months.

2.9.2. Small molecule inhibitors.

In typical embodiments, small molecule JAK inhibitors and small molecule STAT inhibitors are administered orally. In various embodiments, the inhibitor is administered once or twice daily at an oral dose of 0.1-1 mg, 110 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 at a dose of 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg. In accordance with some embodiments, the inhibitor is administered to

- 26 045389 dose of 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg, PO (orally) once or twice a day . In some embodiments, the inhibitor is administered at a dose of 75 mg or 100 mg PO once or twice daily.

2.9.3. Monthly equivalent dose.

In typical embodiments, the IL-6 antagonist is administered at a monthly equivalent dose that is less than the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. The monthly equivalent dose is the calculated total dose administered over a month, regardless of dose size and dosing regimen.

In some embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 50% of the monthly equivalent dose for treating rheumatoid arthritis with the same IL-6 antagonist. In various embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the monthly equivalent dose for the treatment of rheumatoid arthritis with the same IL-6 antagonist. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 45% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 40% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 30% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 25% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 20% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 15% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 10% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of no more than 5% of the monthly equivalent dose for treating rheumatoid arthritis.

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. doses for the treatment of rheumatoid arthritis with the same IL-6 antagonist. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 50% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 40% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 30% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 25% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 20% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 15% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 10% of the monthly equivalent dose for treating rheumatoid arthritis. In certain embodiments, the IL-6 antagonist is administered at a monthly equivalent dose of approximately 5% of the monthly equivalent dose for treating rheumatoid arthritis.

In some embodiments, the IL-6 antagonist is a COR-001 antibody. In various embodiments, COR-001 is administered intravenously at a monthly equivalent dose of 0.5-50 mg, such as 0.5-1 mg, 0.5-2 mg, 0.5-5 mg, 0. 5-10 mg, 0.5-20 mg, 0.5-30 mg, 0.5-40 mg, 1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg , 1-40 mg, 1-50 mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg, 5-10 mg, 5-20 mg , 5-30 mg, 5-40 mg, 5-50 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 20-30 mg, 20-40 mg, 20-50 mg , 30-40 mg, 30-50 mg or 40-50 mg. In certain preferred embodiments, COR-001 is administered intravenously at a monthly equivalent dose of 2-40 mg.

In various embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9

- 27 045389 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 1 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 2 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 3 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 4 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 5 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 6 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 10 mg. In certain embodiments, COR001 is administered intravenously at a monthly equivalent dose of approximately 12 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 15 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 20 mg. In certain embodiments, COR-001 is administered intravenously at a monthly equivalent dose of approximately 40 mg.

In various embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of 1-100 mg, such as 1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 1-70 mg, 1-100 mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg, 2-70 mg, 2-100 mg, 3-5 mg, 3-10 mg, 3-20 mg, 3-30 mg, 3-40 mg, 3-50 mg, 3-70 mg, 3-100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 570 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 certain preferred embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of 3-70 mg. In various embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose 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 certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 1 mg. In certain embodiments, COR001 is administered subcutaneously at a monthly equivalent dose of approximately 2 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 3 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 4 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 5 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 6 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 10 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 12 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 15 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 17 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 20 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 35 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 40 mg. In certain embodiments, COR-001 is administered subcutaneously at a monthly equivalent dose of approximately 70 mg. In certain embodiments, COR001 is administered subcutaneously at a monthly equivalent dose of approximately 100 mg.

In some embodiments, the IL-6 antagonist is siltuximab. In various embodiments, siltuximab is administered intravenously at a monthly equivalent dose of 10-500 mg, such as 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-100 mg, 10- 150 mg, 10-200 mg, 10-300 mg, 10-400 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-100 mg, 20-150 mg, 20-200 mg, 20- 300 mg, 20-400 mg, 20-500 mg, 30-40 mg, 30-50 mg, 30-100 mg, 30-150 mg, 30-200 mg, 30-300 mg, 30-400 mg, 30- 500 mg, 40-50 mg, 40-100 mg, 40-150 mg, 40-200 mg, 40-250 mg, 40-300 mg, 40-400 mg, 40500 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 certain preferred embodiments, siltuximab is administered intravenously at a monthly equivalent dose of 50-500 mg. In accordance with various embodiments, siltuximab is administered intravenously

- 28 045389 equivalent monthly dose 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 certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 50 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 100 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 150 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 200 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 300 mg. In certain embodiments, siltuximab is administered intravenously at a monthly equivalent dose of approximately 500 mg. In various embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of 50-1000 mg, such as 50-80 mg, 50-100 mg, 50-160 mg, 50-200 mg, 50-240 mg, 50-100 mg. 320 mg, 50-480 mg, 50-800 mg, 80-100 mg, 80-160 mg, 80-200 mg, 80-240 mg, 80320 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, 100800 mg, 100-1000 mg, 160-200 mg, 160-240 mg, 160-320 mg, 160 -480 mg, 160-800 mg, 160-1000 mg, 200-240 mg, 200-320 mg, 200-480 mg, 200-800 mg, 200-1000 mg, 240-320 mg, 240-480 mg, 240 -800 mg, 240-1000 mg, 320-480 mg, 320-800 mg, 320-1000 mg, 480-800 mg, 480-1000 mg or 800-1000 mg. In certain preferred embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of 80-800 mg. In various embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 50 mg, 80 mg. 100 mg, 160 mg, 240 mg. 320 mg, 480 mg. 800 mg or 1000 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 50 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 80 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 160 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 240 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 320 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 480 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 800 mg. In certain embodiments, siltuximab is administered subcutaneously at a monthly equivalent dose of approximately 1000 mg.

In some embodiments, the IL-6 antagonist is gerilimzumab. In various embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of 0.05-2 mg, such as 0.05-0.075 mg, 0.05-0.1 mg, 0.050.12 mg, 0.05- 0.3 mg, 0.05-0.6 mg, 0.05-0.9 mg, 0.05-1.8 mg, 0.075-0.1 mg, 0.075-0.12 mg, 0.075-0, 3 mg, 0.075-0.6 mg, 0.075-0.9 mg, 0.075-1.8 mg, 0.075-2 mg, 0.1-0.12 mg, 0.1-0.3 mg, 0.1 -0.6 mg, 0.1-0.9 mg, 0.1-1.8 mg, 0.1-2 mg, 0.12-0.3 mg, 0.12-0.6 mg, 0 ,12-0.9 mg, 0.12-1.8 mg, 0.12-2 mg, 0.3-0.6 mg, 0.3-0.9 mg, 0.3-1.8 mg , 0.3-2 mg, 0.60.9 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 certain preferred embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of 0.075-1.8 mg. In various embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of 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 certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 0.05 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 0.075 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 0.1 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 0.12 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 0.3 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 0.6 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 0.9 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 1.8 mg. In certain embodiments, gerilimzumab is administered intravenously at a monthly equivalent dose of approximately 2 mg. In accordance with various embodiments, gerilimzumab is administered subcutaneously into

- 29 045389 monthly equivalent dose of 0.1-5 mg, such as 0.1-0.125 mg, 0.1-0.15 mg, 0.1-0.2 mg, 0.1-0.5 mg, 0.1-1 mg, 0.1-1.5 mg, 0.1-2 mg, 0.1-3 mg, 0.1-4 mg, 0.125-0.15 mg, 0.125-0, 2 mg, 0.125-0.5 mg, 0.125-1 mg, 0.125-1.5 mg, 0.125-2 mg, 0.125-Zmg, 0.125-4 mg, 0.125-5 mg, 0.15-0.2 mg, 0.15-0.5 mg, 0.15-1 mg, 0.15-1.5 mg, 0.15-2 mg, 0.15-3 mg, 0.15-4 mg, 0.15- 5 mg, 0.2-0.5 mg, 0.2-1 mg, 0.2-1.5 mg, 0.2-2 mg, 0.2-3 mg, 0.2-4 mg, 0 ,2-5 mg, 0.5-1 mg, 0.5-1.5 mg, 0.5-2 mg, 0.5-3 mg, 0.5-4 mg, 0.5-5 mg, 1-1.5 mg, 1-2 mg, 1-3 mg, 1-4 mg, 1-5 mg, 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 certain preferred embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of 0.125-3 mg. In various embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of 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 certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of approximately 0.125 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of approximately

0.2 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of approximately 0.5 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of approximately 1 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of approximately 1.5 mg. In certain embodiments, gerilimzumab is administered subcutaneously at a monthly equivalent dose of approximately 3 mg.

In some embodiments, the IL-6 antagonist is sirukumab. In various embodiments, sirukumab is administered intravenously at a monthly equivalent dose of 1-80 mg, such as 1-1.5 mg, 1-3 mg, 1-6 mg, 1-12 mg, 1-36 mg, 1-60 mg, 1.5-3 mg, 1.5-6 mg, 1.5-12 mg, 1.5-36 mg, 1.5-6o mg, 1.5-80 mg, 3-6 mg, 3-12 mg, 3-36 mg, 3-60 mg, 3-80 mg, 6-12 mg, 6-36 mg, 6-60 mg, 6-80 mg, 12-36 mg, 12-60 mg, 12-80 mg, 36-60 mg, 36-80 mg or 6080 mg. In certain preferred embodiments, sirukumab is administered intravenously at a monthly equivalent dose of 1.5-60 mg. In various embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 1 mg, 1.5 mg, 3 mg, 6 mg, 12 mg, 36 mg, 60 mg, or 80 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 1 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 1.5 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 3 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 6 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 12 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 36 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 60 mg. In certain embodiments, sirukumab is administered intravenously at a monthly equivalent dose of approximately 80 mg.

In various embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of 1-100 mg, such as 1-2.5 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 140 mg, 1-50 mg, 1-60 mg, 2.5-5 mg, 2.5-10 mg, 2.5-20 mg, 2.5-30 mg, 2.5-40 mg, 2, 5-50 mg, 2.5-60 mg, 2.5-100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 5-60 mg, 5 -100 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-60 mg, 10-100 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20 -60 mg, 20-100 mg, 30-40 mg, 30-50 mg, 30-60 mg, 30-100 mg, 40-50 mg, 40-60 mg, 40-100 mg, 50-60 mg, 50 -100 mg or 60-100 mg. In certain preferred embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of 2.5-100 mg. In various embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 100 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 2.5 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 5 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 10 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 20 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 60 mg. In certain embodiments, sirukumab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg.

- 30 045389

In some embodiments, the IL-6 antagonist is clazakizumab. In various embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of 1-80 mg, such as 1-3 mg, 1-6 mg, 1-12 mg, 1-24 mg, 1-36 mg, 1- 60 mg, 3-6 mg, 3-12 mg, 3-24 mg, 3-36 mg, 3-60 mg, 3-80 mg, 6-12 mg, 6-24 mg, 6-36 mg, 6- 60 mg, 6-80 mg, 12-24 mg, 12-36 mg, 12-60 mg, 12-80 mg, 24-36 mg, 24-60 mg, 24-80 mg, 36-60 mg, 36- 80 mg or 60-80 mg. In certain preferred embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of 3-60 mg. In various embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 1 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, 60 mg, or 80 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 1 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 3 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 6 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 12 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 24 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 36 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 60 mg. In certain embodiments, clazakizumab is administered intravenously at a monthly equivalent dose of approximately 80 mg.

In various embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of 1-100 mg, such as 1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1- 40 mg, 1-50 mg, 1-60 mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg, 2-60 mg, 2- 100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 5-60 mg, 5-100 mg, 10-20 mg, 10-30 mg, 10- 40 mg, 10-50 mg, 10-60 mg, 10-100 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-60 mg, 20-100 mg, 30-40 mg, 30-50 mg , 30-60 mg, 30-100 mg, 40-50 mg, 40-60 mg, 40-100 mg, 50-60 mg, 50-100 mg or 60-100 mg. In certain preferred embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of 5-100 mg. In various embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of approximately 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 100 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of approximately 5 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of approximately 10 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of approximately 20 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of approximately 40 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of approximately 60 mg. In certain embodiments, clazakizumab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg.

In some embodiments, the IL-6 antagonist is olokizumab. In various embodiments, olokizumab is administered intravenously at a monthly equivalent dose of 1-80 mg, such as 1-1.8 mg, 1-3.6 mg, 1-9 mg, 1-18 mg, 145 mg, 1-60 mg, 1.8-3.6 mg, 1.8-9 mg, 1.8-18 mg, 1.8-45 mg, 1.8-60 mg, 1.8-80 mg, 3 ,6-9 mg, 3.6-18 mg, 3.6-45 mg, 3.6-60 mg, 3.6-80 mg, 9-18 mg, 9-45 mg, 9-60 mg, 9 -80 mg, 18-45 mg, 18-60 mg, 18-80 mg, 45-60 mg, 45-80 mg or 60-80 mg. In certain preferred embodiments, olokizumab is administered intravenously at a monthly equivalent dose of 1.8-60 mg. In various embodiments, olokizumab is administered intravenously at a monthly equivalent dose of approximately 1 mg, 1.8 mg, 3.6 mg, 9 mg, 18 mg, 45 mg, 60 mg, or 80 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of approximately 1 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of approximately 1.8 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of approximately 3.6 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of approximately 9 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of approximately 18 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of approximately 45 mg. In certain embodiments, olokizumab is administered intravenously at a monthly equivalent dose of approximately 60 mg. In certain embodiments, olokizumab is administered intravenously during the menses

- 31 045389 equivalent dose of approximately 80 mg.

In various embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of 1-100 mg, such as 1-3 mg, 1-6 mg, 1-10 mg, 1-15 mg, 1-20 mg, 1- 30 mg, 1-50 mg, 1-72 mg, 3-6 mg, 3-10 mg, 3-15 mg, 3-20 mg, 3-30 mg, 3-50 mg, 3-72 mg, 3- 100 mg, 6-10 mg, 6-15 mg, 6-20 mg, 6-30 mg, 6-50 mg, 6-72 mg, 6-100 mg, 10-15 mg, 10-20 mg, 10- 30 mg, 10-50 mg, 10-72 mg, 10-100 mg, 15-20 mg, 15-30 mg, 15-50 mg, 15-72 mg, 15-100 mg, 20-30 mg, 20-50 mg , 20-72 mg, 20-100 mg, 30-50 mg, 30-72 mg, 30-100 mg, 50-72 mg, 50-100 mg or 72-100 mg. In certain preferred embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of 3-100 mg. In various embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of approximately 1 mg, 3 mg, 6 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, 72 mg, or 100 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of approximately 3 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of approximately 6 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of approximately 15 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of approximately 30 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of approximately 72 mg. In certain embodiments, olokizumab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg.

In some embodiments, the IL-6 antagonist is tocilizumab. In various embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of 10-500 mg, such as 10-20 mg, 10-50 mg, 10-100 mg, 10-150 mg, 10-200 mg, 10-250 mg , 10-300 mg, 10-350 mg, 10-400 mg, 20-50 mg, 20-100 mg, 20-150 mg, 20-200 mg, 20-250 mg, 20-300 mg, 20-350 mg , 20-400 mg, 20-500 mg, 50-100 mg, 50-150 mg, 50-200 mg, 50-250 mg, 50-300 mg, 50-350 mg, 50-400 mg, 50-500 mg , 100-150 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 100-400 mg, 100-500 mg, 150-200 mg, 150-250 mg, 150-300 mg , 150-350 mg, 150-400 mg, 150-500 mg, 200-250 mg, 200-300 mg, 200-350 mg, 200-400 mg, 200-500 mg, 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 certain preferred embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of 50-500 mg. In various embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of 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 certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 50 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 100 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 150 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 250 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 350 mg. In certain embodiments, tocilizumab is administered intravenously at a monthly equivalent dose of approximately 500 mg.

In various embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of 50-1000 mg, such as 50-80 mg, 50-160 mg, 50-240 mg, 50-400 mg, 50-560 mg, 50- 800 mg, 80-160 mg, 80-240 mg, 80-400 mg, 80-560 mg, 80-800 mg, 80-1000 mg, 160-240 mg, 160-400 mg, 160-560, 160-800 mg, 160-1000 mg, 240-400 mg, 240-560 mg, 240-800 mg, 240-1000 mg, 400-560 mg, 400-800 mg, 400-1000 mg, 560-800 mg, 560-1000 mg or 800-100 mg. In certain preferred embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of 80-800 mg. In various embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 50 mg, 80 mg, 160 mg, 240 mg, 400 mg, 560 mg, 800 mg, or 1000 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 50 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 80 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 160 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 240 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 400 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 560 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 800 mg. In certain embodiments, tocilizumab is administered subcutaneously at a monthly equivalent dose of approximately 1000 mg.

In some embodiments, the IL-6 antagonist is sarilumab. In various embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 10-150 mg, such as 10-12 mg, 10-24 mg, 10-48 mg, 10-60 mg, 10-72 mg, 10- 120 mg, 12-24 mg, 12-48 mg, 12-60 mg, 12-72 mg, 12-120 mg, 12-150 mg, 24-48 mg, 24-60 mg, 24-72 mg, 24- 120 mg, 24-150 mg, 48-60 mg, 48-72 mg, 48-120 mg, 48-150 mg, 60-72 mg, 60-120 mg, 60-150 mg, 72-120 mg, 72-150 mg or 120-150 mg. In certain preferred embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 12,120 mg. In various embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 10 mg, 12 mg, 24 mg, 48 mg, 60 mg, 72 mg, 120 mg, or 150 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 10 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 12 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 24 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 48 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 60 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 72 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 120 mg. In certain embodiments, sarilumab is administered intravenously at a monthly equivalent dose of 150 mg. In various embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of 10-200 mg, such as 10-20 mg, 10-40 mg, 10-60 mg, 10-80 mg, 10-100 mg, 10- 120 mg, 20-40 mg, 20-60 mg, 20-80 mg, 20-100 mg, 20120 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. In certain preferred embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of 20-200 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 certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 20 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 40 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 80 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 120 mg. In certain embodiments, sarilumab is administered subcutaneously at a monthly equivalent dose of approximately 200 mg.

In some embodiments, the IL-6 antagonist is vobarilizumab. In various embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of 2-150 mg, such as 2-4 mg, 2-6 mg, 2-30 mg, 2-60 mg, 284 mg, 2-120 mg. , 4-6 mg, 4-30 mg, 4-60 mg, 4-84 mg, 4-120 mg, 4-150 mg, 6-30 mg, 6-60 mg, 6-84 mg, 6-120 mg , 6150 mg, 30-60 mg, 30-84 mg, 30-120 mg, 30-150 mg, 60-84 mg, 60-120 mg, 60-150 mg, 84-120 mg, 84-150 mg or 120 -150 mg. In certain preferred embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of 4-120 mg. In various embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 2 mg, 4 mg, 6 mg, 30 mg, 60 mg, 84 mg, 120 mg, or 150 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 2 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 4 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 6 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 30 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 60 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 84 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of

- 33 045389 approximately 120 mg. In certain embodiments, vobarilizumab is administered intravenously at a monthly equivalent dose of approximately 150 mg.

In various embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of 5-200 mg, such as 5-7 mg, 5-10 mg, 5-20 mg, 5-50 mg, 5-70 mg, 5- 100 mg, 5-140 mg, 7-10 mg, 7-20 mg, 7-50 mg, 7-70 mg, 7-10o mg, 7-140 mg, 7-200 mg, 10-20 mg, 10- 50 mg, 1070 mg, 10-100 mg, 10-140 mg, 10-200 mg, 20-50 mg, 20-70 mg, 20-100 mg, 20-140 mg, 20-200 mg, 50-70 mg , 50-100 mg, 50-140 mg, 50-200 mg, 70-100 mg, 70-140 mg, 70-200 mg, 100-140 mg, 100-200 mg or 140-200 mg. In certain preferred embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of 7-200 mg. In various embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 5 mg, 7 mg, 10 mg, 20 mg, 40 mg, 50 mg, 70 mg, 100 mg, 140 mg, or 200 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 7 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 10 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 50 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 100 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 140 mg. In certain embodiments, vobarilizumab is administered subcutaneously at a monthly equivalent dose of approximately 200 mg.

3. Examples

The following examples are provided for purposes of explanation by example and illustration and not limitation.

3.1. Example 1: Phase 1/2 clinical trial.

A phase 1/2 clinical study was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of multiple IV doses of COR-001.

3.1.1. Medicine (COR-001).

COR-001 is a human IgG1-kappa antibody directed against interleukin-6 (IL-6). COR-001 contains a YTE mutation in its Fc region. The sequence and other characteristics of COR-001 are described in section 2.7.1.1 above.

3.1.2. Research plan.

The study was a randomized, double-blind, placebo-controlled trial designed to evaluate the safety, pharmacokinetic characteristics, and pharmacodynamic effects of multiple doses of COR-001 (MEDI5117) or placebo administered to consecutive cohorts of hemodialysis patients.

Key inclusion criteria include chronic kidney disease stage 5 (CKD-5) with hemodialysis, TMPRSS6 736A genotype positivity (major allele), IL-6 level greater than 4 pg/ml, and erythropoietin resistance index greater than 8.

Ten hemodialysis patients were randomized to receive COR-001 or placebo in each dose cohort. When a dose higher than that studied in the previous cohort was initiated, the first 2 patients (sentinel) in that cohort (randomized 1:1 to receive COR-001 or placebo) were randomized first, and the remaining patients were randomized at least 48 hours later in the ratio COR-001 and placebo, 7:1. The final ratio of patients treated with COR-001 versus placebo was 8:2 in each cohort of 10 patients. The maximum tolerated dose (MTD) estimate was based on safety data from Week 1 to Week 3. If more than 2 of 8 active patients in the cohort experienced dose-limiting toxicity (DLT), the MTD was considered to have been exceeded. The dose escalation scheme is shown in Fig. 1. COR-001 was administered as an intravenous infusion, starting any time before the last 1 hour of dialysis therapy. Dosage regimens for COR-001 are presented in table. 1 below.

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Table 1

Cohort by dose Dosage schedule Number of doses Total cumulative dose 1 2 mg every 14 days 6 12 mg 2 6 mg every 14 days 6 36 mg 3 6 mg every 14 days 6 36 mg 4 2 mg every 14 days 6 12 mg 5 20 mg every 14 days 6 120 mg 6 20 mg every 14 days 6 120 mg

The total study duration for an individual patient was approximately 9 months, excluding the screening period of up to 4 weeks. As shown in FIG. 2, the study included a treatment period of 12 weeks (Week 1 to Week 12), a safety follow-up period of 12 weeks (Week 13 to Week 24), and an extended follow-up period of 10 weeks (Week 1 to Week 12). from Week 25 to Week 35).

Interim data collected during the study were summarized by treatment group for appropriate population analysis using descriptive statistics parameters. Descriptive statistics parameters for continuous variables included number of patients (n), mean, standard deviation (SD), median, quartiles (Q1 and Q3), minimum (min) and maximum (max) values. Analysis of categorical variables included frequencies and percentages.

Changes in high sensitivity C-reactive protein (hsCRP), absolute neutrophil count (ANC), lipoprotein(a) level, LDL level, hemoglobin, transferrin saturation (TSAT), albumin level, erythropoietin resistance index (ERI), dynamic hand strength, NTproBNP, and cardiac MRI were recorded throughout the study.

3.1.3. Analysis of clinical data.

Assays were performed to determine the effect of COR-001 on C-reactive protein (CRP), the effect of COR-001 on hemoglobin levels, the effect of COR-001 on various cardiac parameters, and the effect of COR-001 on neutrophil and platelet levels.

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

The percentages of patients with mean post-treatment hsCRP <2 mg/L at Week 12 were 44%, 62% and 85% in the 2 mg, 6 mg and 20 mg groups, respectively, according to compared with 14% in the placebo group. Analysis of hsCRP in responders demonstrates that COR-001 (an anti-IL-6 antibody) has a better effect on hsCRP than that reported for canakinumab (an anti-IL1 β antibody) in the CANTOS trial. Response rates to hsCRP for COR-001 in dialysis patients with stage 5 chronic kidney disease at IV doses of 20 mg and 6 mg (Figure 3A) were higher than response rates to hsCRP for canakinumab at equivalent doses in the CANTOS trial (Figure 3B). The in vivo IC50 concentration of COR-001 for CRP (50% reduction from baseline CRP) is 206 ng/mL.

COR-001 improved a key indicator of anemia - hemoglobin levels. Analysis of the treatment response in the form of hemoglobin level indicated a dose-dependent response to treatment in the form of hemoglobin level in the case of treatment with COR-001 (Fig. 4).

The effect of COR-001 on various biological markers of heart failure was determined. As shown in FIG. 5, COR-001 decreased the level of N-terminal prohormone brain natriuretic peptide (NT-proBNP). The result indicates that treatment with COR-001 may reduce heart failure.

Anti-inflammatory therapeutic agents in general, and IL-6 inhibitory therapeutic agents in particular, pose a risk of inducing immunosuppression, thereby facilitating the occurrence of infections, sometimes serious in nature.

Immunosuppression can be measured by the number of neutrophils. The effect of COR-001 on neutrophil counts was determined.

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Claims (6)

Surprisingly, despite the significant reduction in inflammation as measured by hsCRP levels (Fig. 3A), the absolute neutrophil count in patients treated with COR-001 did not fall below normal levels. No opportunistic infections were observed during treatment. As shown in FIG. 6A, the percentage of patients with absolute neutrophil counts below 2.0 x 10 ⁹ /L did not increase with COR-001 at all study doses compared to the placebo group. All patients treated with COR-001 at all study doses had an absolute neutrophil count greater than 1.5 x 10 ⁹ /L. The in vivo IC50 concentration of COR-001 for neutrophil count (50% reduction from baseline neutrophil count) is 5540 ng/mL. The percentages of patients with platelet counts below 100 x 10 ⁹ /L were less than 30% with COR001 at all doses studied (Fig. 6B). The in vivo IC50 concentration of COR-001 for platelet count (50% reduction from baseline platelet count) is 13,800 ng/mL. In summary, clinical data indicate that treatment with COR-001 at doses of 2 mg, 6 mg and 20 mg may reduce inflammation without inducing immunosuppression in dialysis patients with chronic kidney disease stage 5 (CKD-5) , while the absolute neutrophil count did not decrease significantly in patients treated with COR-001. Administration of COR-001 reduced CRP levels in a dose-dependent manner. Additionally, COR-001 increased hemoglobin levels in these patients. COR-001 reduced the level of the biological marker of heart failure NT-proBNP. 4. Incorporation by reference All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication, patent, patent application or the other document has been separately incorporated by reference. 5. Equivalents Although various specific embodiments have been illustrated and described, the foregoing description is not limiting. It will be understood that various changes may be made without departing from the spirit and scope of the present invention. Many variations will become apparent to those skilled in the art upon reading this disclosure. CLAIM 1. A method of treating a cardiovascular disease in a patient, comprising administering an IL-6 antagonist to a patient with IL-6-mediated inflammation, wherein said IL-6 antagonist is COR-001 and COR-001 is administered subcutaneously at a monthly equivalent dose of 4 up to 40 mg; where said patient has stage 3-5 chronic kidney disease according to the KDOQI classification. 2. The method according to claim 1, wherein COR-001 is administered subcutaneously at a monthly equivalent dose of 5 to 40 mg. 3. The method according to claim 1, wherein COR-001 is administered subcutaneously at a monthly equivalent dose of 10 to 30 mg. 4. The method according to claim 1, wherein COR-001 is administered subcutaneously at a monthly equivalent dose of 10 to 20 mg. 5. Method according to any one of claims 1 to 4, wherein the level of C-reactive protein (CRP) in the patient before treatment is at least 2 mg/l. 6. Method according to any one of claims 1 to 5, wherein the level of IL-6 in the blood serum of the patient before treatment is at least 2 pg/ml. -