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

Abstract

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 rheumatoid arthritis and associated conditions, methods of treating systemic lupus erythematosus and associated conditions, and methods of treating multiple sclerosis.

1 . A method of treating a condition associated with rheumatoid arthritis comprising administering an antibody that binds colony stimulating factor 1 receptor (CSF1R) to a subject with rheumatoid arthritis, wherein the antibody blocks binding of colony stimulating factor 1 (CSF1) to CSF1R and blocks binding of IL-34 to CSF1R, and wherein treating a condition associated with rheumatoid arthritis comprises at least one effect selected from reducing inflammation, reducing pannus formation, reducing cartilage damage, reducing bone resorption, reducing the number of macrophages in at least one joint affected by rheumatoid arthritis, reducing autoantibody levels, and reducing bone loss. 
     
     
         2 . The method of  claim 1 , wherein treating a condition associated with rheumatoid arthritis comprises reducing inflammation. 
     
     
         3 . The method of  claim 2 , wherein the number of CD16+ monocytes is reduced by at least 30%. 
     
     
         4 . The method of  claim 3 , wherein the number of CD16− monocytes is not reduced or is reduced by less than 20%. 
     
     
         5 . The method of  claim 2 , wherein the method further comprises determining an erythrocyte sedimentation rate, wherein a reduced sedimentation rate indicates reduced inflammation. 
     
     
         6 . The method of  claim 1 , wherein treating a condition associated with rheumatoid arthritis comprises at least one effect selected from reducing pannus formation, reducing bone resorption, and reducing bone loss. 
     
     
         7 . The method of  claim 6 , wherein treating a condition associated with rheumatoid arthritis comprises reducing bone resorption. 
     
     
         8 . The method of  claim 7 , wherein the level of at least one marker of bone resorption is reduced. 
     
     
         9 . The method of  claim 8 , wherein the bone resorption marker is selected from tartrate resistant acid phosphatase 5b (TRAP5b), urinary total pyridinoline, Urinary total deoxypyridinoline, urinary free pyridinoline, serum collagen type I cross-linked N-telopeptide, urinary collagen type I cross-linked N-telopeptide, and serum carboxyterminal telopeptide of type I collagen. 
     
     
         10 . The method of  claim 6 , wherein treating a condition associated with rheumatoid arthritis comprises at least one effect selected from reducing pannus formation, and reducing bone loss. 
     
     
         11 . The method of  claim 10 , wherein the at least one effect is measured using an imaging technique. 
     
     
         12 . The method of  claim 11 , wherein the imaging technique comprises a method selected from x-ray imaging, magnetic resonance imaging, computed tomography (CT) scan, arthroscopy, scintigraphy, ultrasonography, bone densitometry, single photon absorptiometry (SPA), dual photon absorptiometry (DPA), single energy x-ray absorptiometry (SXA), dual energy x-ray absorptiometry (DXA), scintigraphy, ultrasonography, duplex ultrasonography, and power doppler imaging. 
     
     
         13 . A method of treating a condition selected from rheumatoid arthritis, lupus, an inflammatory condition, and a CD 16+disorder comprising administering an antibody that binds CSF1R to a subject with the condition, wherein the antibody blocks binding of CSF1 to CSF1R and blocks binding of IL-34 to CSF1R, and wherein the antibody reduces the number of CD16+ monocytes in the subject by at least 30%, and wherein CD16− monocytes are not reduced or are reduced by less than 20%. 
     
     
         14 . The method of  claim 1 , wherein the method further comprises administering at least one additional therapeutic agent selected from methotrexate, an anti-TNF agent, a glucocorticoid, cyclosporine, leflunomide, azathioprine, a JAK inhibitor, a SYK inhibitor, an anti-IL-6 antibody, an anti-IL-6R antibody, an anti-CD-20 antibody, an anti-CD19 antibody, an anti-GM-CSF antibody, an IL-1 receptor antagonist, a CTLA-4 antagonist, and an anti-GM-CSF-R antibody. 
     
     
         15 . A method of treating lupus nephritis and/or skin lesions associated with lupus and/or slowing progression of a kidney condition associated with lupus comprising administering an antibody that binds CSF1R to a subject with lupus, wherein the antibody blocks binding of CSF1 to CSF1R and blocks binding of IL-34 to CSF1R, and wherein treating skin lesions associated with lupus comprises at least one effect selected from reducing the number of skin lesions, reducing the rate of formation of skin lesions, and reducing the severity of skin lesions. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 15 , wherein kidney function is improved in the subject. 
     
     
         18 . The method of  claim 15 , wherein proteinuria is reduced in the subject. 
     
     
         19 . The method of  claim 15 , wherein glomerular filtration rate is improved in the subject. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 13 , wherein CD16+ monocytes are reduced by at least 50%. 
     
     
         22 . The method of  claim 13 , wherein the method further comprises administering at least one additional therapeutic agent selected from hydroxychloroquine (Plaquenil), a corticosteroids, cyclophosphamide (Cytoxan), azathioprine (Imuran, Azasan), mycophenolate (Cellcept), leflunomide (Arava) and methotrexate (Trexall), and belimumab (Benlysta). 
     
     
         23 - 26 . (canceled) 
     
     
         27 . The method of  claim 13 , wherein the rheumatoid arthritis, lupus, inflammatory condition, or CD16+ disorder does not respond to methotrexate. 
     
     
         28 . A method of reducing the number of CD16+ monocytes comprising administering an antibody that binds CSF1R to a subject, wherein the antibody blocks binding of CSF1 to CSF1R and blocks binding of IL-34 to CSF1R, and wherein the antibody reduces the number of CD16+ monocytes by at least 30%, and wherein CD16− monocytes are not reduced or are reduced by less than 20%. 
     
     
         29 . The method of  claim 28 , wherein CD16+ monocytes are reduced by at least 50%. 
     
     
         30 . The method of  claim 13 , wherein the CD16+ monocytes are CD16+ peripheral blood monocytes. 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 15 , wherein proteinuria does not increase in the subject or does not increase in the subject at the same rate as in subjects not administered the antibody. 
     
     
         33 . The method of  claim 15 , wherein glomerular filtration rate does not decrease in the subject or does not decrease in the subject at the same rate as in a subjects not administered the antibody. 
     
     
         34 . A method of slowing the progression of pannus formation and/or bone loss in a subject with rheumatoid arthritis, comprising administering an antibody that binds colony stimulating factor 1 receptor (CSF1R) to a subject with rheumatoid arthritis, wherein the antibody blocks binding of colony stimulating factor 1 (CSF1) to CSF1R and blocks binding of IL-34 to CSF1R. 
     
     
         35 . (canceled) 
     
     
         36 . 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.   
     
     
         37 . The method of  claim 36 , wherein the antibody is a humanized antibody. 
     
     
         38 . The method of  claim 36 , wherein the antibody is selected from a Fab, an Fv, an scFv, a Fab′, and a (Fab′) 2 .