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 .- 69 . (canceled) 
     
     
         70 . A method of reducing the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 in a subject with CD16+ disorder, comprising (a) determining that the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 is elevated in the subject, and (b) administering to the subject an effective amount of an antibody to reduce the level of the at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 in the subject, wherein the antibody binds human colony stimulating factor 1 receptor (CSF1R) and blocks binding of human colony stimulating factor 1 (CSF1) to human CSF1R and blocks binding of human IL-34 to human CSF1R. 
     
     
         71 . The method of  claim 70 , wherein the antibody comprises 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. 
     
     
         72 . The method of  claim 70 , further comprising (c) determining the level of the at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 in the subject following administration of the antibody to detect reduction of said level. 
     
     
         73 . The method of  claim 70 , wherein the method comprises reducing the level of at least one factor selected from IL-6 and IL-1β. 
     
     
         74 . The method of  claim 73 , wherein the method comprises reducing the level of IL-6. 
     
     
         75 . The method of  claim 70 , wherein the antibody inhibits ligand-induced CSF1R phosphorylation in vitro. 
     
     
         76 . The method of  claim 70 , wherein the antibody is a humanized antibody. 
     
     
         77 . The method of  claim 70 , wherein the antibody is a Fab, an Fv, an scFv, a Fab′, or a (Fab′) 2 . 
     
     
         78 . The method of  claim 70 , wherein the method comprises administering at least one additional therapeutic agent to the subject. 
     
     
         79 . The method of  claim 70 , wherein the antibody comprises a full-length heavy chain and a full-length light chain. 
     
     
         80 . The method of  claim 79 , wherein the antibody is an IgG antibody. 
     
     
         81 . The method of  claim 80 , wherein the antibody is an IgG4 antibody. 
     
     
         82 . The method of  claim 81 , wherein the IgG4 antibody comprises an S241P mutation. 
     
     
         83 . The method of  claim 70 , wherein an elevated protein level of the at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 is determined. 
     
     
         84 . The method of  claim 70 , wherein an elevated mRNA level of the at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 is determined. 
     
     
         85 . The method of  claim 70 , further comprising determining the level of CD16+ monocytes in the subject before and/or after administration of the antibody. 
     
     
         86 . A method of reducing the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 in a subject with a CD16+ disorder, comprising (a) determining that the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 is elevated in the subject, and (b) administering to the subject an effective amount of an antibody to reduce the level of the at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 in the subject, wherein the antibody binds human colony stimulating factor 1 receptor (CSF1R) and blocks binding of human colony stimulating factor 1 (CSF1) to human CSF1R and blocks binding of human IL-34 to human CSF1R, and wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 39 and a light chain comprising the sequence of SEQ ID NO: 46. 
     
     
         87 . The method of  claim 86 , wherein the antibody is a Fab, an Fv, an scFv, a Fab′, or a (Fab′) 2 . 
     
     
         88 . The method of  claim 87 , wherein the antibody is an IgG4 antibody comprising an S241P mutation. 
     
     
         89 . A method of reducing the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 in a subject with a CD16+ disorder, comprising (a) determining that the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 is elevated in the subject, and (b) administering to the subject an effective amount of an antibody to reduce the level of the at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 in the subject, wherein the antibody binds human colony stimulating factor 1 receptor (CSF1R) and blocks binding of human colony stimulating factor 1 (CSF1) to human CSF1R and blocks binding of human IL-34 to human CSF1R, and wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 53 and a light chain comprising the sequence of SEQ ID NO: 60. 
     
     
         90 . The method of  claim 70 , wherein the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 is determined in a blood sample from the subject. 
     
     
         91 . The method of  claim 86 , wherein the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 is determined in a blood sample from the subject. 
     
     
         92 . The method of  claim 89 , wherein the level of at least one factor selected from IL-6, IL-1β, IL-8, CCL2, CCL7, CXCL5, CXCL6, MMP-7, MMP-2, and MMP-9 is determined in a blood sample from the subject.