Methods of treating conditions with antibodies that bind colony stimulating factor 1 receptor (csf1r)

Abstract

Methods of reducing cytokine levels and methods of treating conditions with antibodies that bind colony stimulating factor 1 receptor (CSF1R) are provided. Such methods include, but are not limited to, methods of treating inflammatory conditions, such as rheumatoid arthritis.

1 . A method of reducing the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CXCL10, TNF-α, CCL7, CXCL5, CXCL9, CXCL6, MMP-7, MMP-2, and MMP-9 in a subject, comprising administering an effective amount of an antibody that binds colony stimulating factor 1 receptor (CSF1R) to the subject, wherein the antibody blocks binding of colony stimulating factor 1 (CSF1) to CSF1R and blocks binding of IL-34 to CSF1R. 
     
     
         2 . The method of  claim 1 , wherein the method comprises reducing the level of at least one factor selected from IL-6, IL-1β, TNF-α, and CXCL10. 
     
     
         3 . The method of  claim 1 , wherein the method comprises reducing the level of IL-6. 
     
     
         4 . The method of  claim 3 , wherein the subject has a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, and Castleman's disease. 
     
     
         5 . The method of  claim 1 , wherein the method comprises reducing the level of TNF-α. 
     
     
         6 . The method of  claim 5 , wherein the subject has a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis. 
     
     
         7 . The method of  claim 1 , wherein the method comprises reducing the level of IL-1β. 
     
     
         8 . The method of  claim 7 , wherein the subject has a condition selected from rheumatoid arthritis and juvenile idiopathic arthritis. 
     
     
         9 . The method of  claim 1 , wherein the method comprises reducing the level of CXCL10. 
     
     
         10 .- 26 . (canceled) 
     
     
         27 . A method of treating an inflammatory condition comprising administering an effective amount of an antibody that binds CSF1R to a subject with an inflammatory condition, wherein the antibody blocks binding of CSF1 to CSF1R and blocks binding of IL-34 to CSF1R, and wherein the antibody reduces the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CXCL10, TNF-α, CCL7, CXCL5, CXCL9, CXCL6, MMP-7, MMP-2, and MMP-9. 
     
     
         28 . The method of  claim 27 , wherein the antibody reduces the level of at least one factor selected from IL-6, IL-1β, TNF-α, and CXCL10. 
     
     
         29 . The method  claim 27 , wherein the antibody reduces the level of IL-6. 
     
     
         30 . The method of  claim 27 , wherein the antibody reduces the level of TNF-α. 
     
     
         31 . The method of  claim 27 , wherein the antibody reduces the level of IL-1β. 
     
     
         32 . The method of  claim 27 , wherein the antibody reduces the level of CXCL10. 
     
     
         33 . The method of  claim 27 , wherein the inflammatory condition is selected from rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis, lupus erythematosus, and inflammatory bowel disease. 
     
     
         34 . A method of treating CD16+ disorder comprising administering an effective amount of an antibody that binds CSF1R to a subject with a CD16+ disorder, wherein the antibody blocks binding of CSF1 to CSF1R and blocks binding of IL-34 to CSF1R, and wherein the antibody reduces the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CXCL10, TNF-α, CCL7, CXCL5, CXCL9, CXCL6, MMP-7, MMP-2, and MMP-9. 
     
     
         35 . The method of  claim 34 , wherein the antibody reduces the level of at least one factor selected from IL-6, IL-1β, TNF-α, and CXCL10. 
     
     
         36 . The method  claim 34 , wherein the antibody reduces the level of IL-6. 
     
     
         37 . The method of  claim 34 , wherein the antibody reduces the level of TNF-α. 
     
     
         38 . The method of  claim 34 , wherein the antibody reduces the level of IL-1β. 
     
     
         39 . The method of  claim 34 , wherein the antibody reduces the level of CXCL10. 
     
     
         40 . The method of  claim 34 , wherein the CD16+ disorder is selected from rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis, lupus erythematosus, and inflammatory bowel disease. 
     
     
         41 . The method of  claim 34 , wherein the antibody substantially reduces the number of CD16+ monocytes. 
     
     
         42 . The method of  claim 41 , wherein the number of CD16− monocytes are substantially unchanged following administration of the antibody. 
     
     
         43 . The method of  claim 27 , wherein the antibody reduces the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CXCL10, TNF-α, CCL7, CXCL5, CXCL9, CXCL6, MMP-7, MMP-2, and MMP-9 in vitro. 
     
     
         44 . The method of  claim 27 , wherein the subject has an elevated level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CXCL10, TNF-α, CCL7, CXCL5, CXCL9, CXCL6, MMP-7, MMP-2, and MMP-9 prior to administration of the antibody. 
     
     
         45 . The method of  claim 27 , wherein the condition is resistant to methotrexate and/or wherein the subject is a methotrexate inadequate responder. 
     
     
         46 . The method of  claim 27 , wherein the condition is resistant to a TNF inhibitor and/or the subject is a TNF inhibitor inadequate responder. 
     
     
         47 .- 61 . (canceled) 
     
     
         62 . The method of  claim 27 , wherein the method further comprises administering at least one additional therapeutic agent selected from a DMARD, methotrexate, a TNF inhibitor, an anti-TNF agent, a glucocorticoid, cyclosporine, leflunomide, azathioprine, a JAK inhibitor, a SYK inhibitor, an anti-IL-6 agent, an anti-CD20 agent, an anti-CD19 agent, an anti-GM-CSF agent, an anti-IL-1 agent, and a CTLA4 agent. 
     
     
         63 . The method of  claim 62 , wherein the at least one additional therapeutic agent is selected from methotrexate, an anti-TNF-α antibody, a soluble TNF receptor, a glucocorticoid, cyclosporine, leflunomide, azathioprine, a JAK inhibitor, a SYK inhibitor, an anti-IL-6 antibody, an anti-IL-6 receptor antibody, an anti-CD20 antibody, an anti-CD19 antibody, an anti-GM-CSF antibody, and anti-GM-CSF receptor antibody, an anti-IL-1 antibody, an IL-1 receptor antagonist, and a CTLA4-Ig fusion molecule. 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . The method of  claim 1 , wherein the antibody inhibits ligand-induced CSF1R phosphorylation in vitro. 
     
     
         67 . The method of  claim 1 , wherein the antibody is selected from:
 a) an antibody comprising a heavy chain comprising the sequence of SEQ ID NO: 39 and a light chain comprising the sequence of SEQ ID NO: 46;   b) an antibody comprising a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 15, an HC CDR2 having the sequence of SEQ ID NO: 16, and an HC CDR3 having the sequence of SEQ ID NO: 17, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 18, a LC CDR2 having the sequence of SEQ ID NO: 19, and a LC CDR3 having the sequence of SEQ ID NO: 20; and   c) an antibody comprising a heavy chain comprising the sequence of SEQ ID NO: 53 and a light chain comprising the sequence of SEQ ID NO: 60.   
     
     
         68 . The method of  claim 67 , wherein the antibody is a humanized antibody. 
     
     
         69 . The method of  claim 67 , wherein the antibody is selected from a Fab, an Fv, an scFv, a Fab′, and a (Fab′) 2 . 
     
     
         70 . The method of  claim 34 , wherein the condition is resistant to methotrexate and/or wherein the subject is a methotrexate inadequate responder. 
     
     
         71 . The method of  claim 34 , wherein the condition is resistant to a TNF inhibitor and/or the subject is a TNF inhibitor inadequate responder.