Anti-IL 17A/IL-17F Cross-Reactive Antibodies and Methods of Use Thereof

Abstract

This invention provides fully human monoclonal antibodies that recognize IL-17F, the IL-17F homodimer, IL-17A, the IL-17A homodimer, and/or the heterodimeric IL-17A/IL-17F protein complex. The invention further provides methods of using such monoclonal antibodies as a therapeutic, diagnostic, and prophylactic.

1 . An isolated fully human monoclonal antibody that binds IL-17A homodimer, IL-17F homodimer and the IL-17A/IL-17F heterodimeric complex, wherein the antibody exhibits (i) a binding affinity of at least 100 pM or less against the IL-17A homodimer, (ii) a binding affinity of at least 300 pM or less against the IL-17F homodimer, (iii) a binding affinity of at least 400 pM or less against the IL-17A/IL-17F heterodimeric complex, (iv) a neutralizing ability of at least 13 nM or less against the IL-17A homodimer, (v) a neutralizing ability of at least 120 nM or less against the IL-17F homodimer, and (vi) a neutralizing ability of at least 31 nM or less against the IL-17A/IL-17F heterodimeric complex. 
     
     
         2 . The antibody of  claim 1 , wherein the antibody exhibits (i) a binding affinity of at least 40 pM or less against the IL-17A homodimer, (ii) a binding affinity of at least 10 pM or less against the IL-17F homodimer, and (iii) a binding affinity of at least 50 pM or less against the IL-17A/IL-17F heterodimer. 
     
     
         3 . The antibody of  claim 1 , wherein the antibody exhibits (i) a binding affinity of at least 15 pM or less against the IL-17A homodimer, (ii) a binding affinity of at least 10 pM or less against the IL-17F homodimer, and (iii) a binding affinity of at least 30 pM or less against the IL-17A/IL-17F heterodimer. 
     
     
         4 . The antibody of  claim 1 , wherein the antibody exhibits, (iv) a neutralizing ability of at least 13 nM or less against the IL-17A homodimer, (v) a neutralizing ability of at least 1.9 nM or less against the IL-17F homodimer, and (vi) a neutralizing ability of at least 11 nM or less against the IL-17A/IL-17F heterodimeric complex. 
     
     
         5 . The antibody of  claim 1 , wherein the antibody exhibits, (iv) a neutralizing ability of at least 1.6 nM or less against the IL-17A homodimer, (v) a neutralizing ability of at least 1.7 nM or less against the IL-17F homodimer, and (vi) a neutralizing ability of at least 1.1 nM or less against the IL-17A/IL-17F heterodimeric complex. 
     
     
         6 . The antibody of  claim 1 , wherein the antibody exhibits, (iv) a neutralizing ability of at least 0.2 nM or less against the IL, 17A homodimer, (v) a neutralizing ability of at least 1.2 nM or less against the IL-17F homodimer, and (vi) a neutralizing ability of at least 0.2 nM or less against the IL-17A/IL-17F heterodimeric complex. 
     
     
         7 . The antibody of  claim 1 , wherein the antibody is 15E6 and comprises a VH CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 85, a VH CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 86, a VH CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 87, a VL CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 110, a VL CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 97 and a VL CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 111. 
     
     
         8 . The antibody of  claim 1 , wherein the antibody is 15E6FK and comprises a VH CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 85, a VH CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 94, a VH CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 95, a VL CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 110, a VL CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 97 and a VL CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 111. 
     
     
         9 . The antibody of  claim 1 , wherein the antibody binds to the same epitope as the 15E6 antibody. 
     
     
         10 . The antibody of  claim 1 , wherein the antibody binds to the same epitope as the 15E6FK antibody. 
     
     
         11 . The antibody of  claim 1 , wherein the antibody binds IL-17A, IL-17F and the IL-17A/IL-17F heterodimeric complex and prevents one or more of IL-17F, IL-17A or the IL-17A/IL-17F heterodimeric complex from binding with its receptor. 
     
     
         12 . An isolated fully human monoclonal antibody, or fragment thereof, wherein said antibody comprises:
 (a) a V H  CDR1 region comprising the amino acid sequence of SEQ ID NO: 57, 60, 66, 69, 76, 79, 82, or 85;   (b) a V H  CDR2 region comprising the amino acid sequence of SEQ ID NO: 58, 61, 63, 65, 67, 70, 72, 74, 77, 80, 83, 86, 93 or 94;   (c) a V H  CDR3 region comprising the amino acid sequence of SEQ ID NO: 59, 62, 64, 68, 71, 73, 75, 78, 81, 84, 87, or 95;   (d) a V L  CDR1 region comprising the amino acid sequence of SEQ ID NO: 96, 101, 104, 107 or 110;   (e) a V L  CDR2 region comprising the amino acid sequence of SEQ ID NO: 97, 102, 105 or 108; and   (f) a V L  CDR3 region comprising the amino acid sequence of SEQ ID NO: 98, 99, 100, 103, 106, 109, or 111,   wherein said antibody binds IL-17F and IL-17A.   
     
     
         13 . The antibody of  claim 12 , wherein said antibody also binds the IL-17A/IL-17F heterodimeric complex. 
     
     
         14 . The antibody of  claim 12 , wherein said antibody is an IgG isotype. 
     
     
         15 . The antibody of  claim 12 , wherein said antibody is an IgG1 isotype. 
     
     
         16 . The antibody of  claim 12 , wherein said antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2, 6, 8, 10, 14, 18, 20, 24, 28, 32, 34, 38, 52, and 54. 
     
     
         17 . The antibody of  claim 12 , wherein said antibody further comprises a light chain variable sequence comprising the amino acid sequence selected from SEQ ID NO: 4, 12, 16, 22, 26, 30, 36, 40 and 56. 
     
     
         18 . An isolated fully human monoclonal antibody comprising a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO: 2, 6, 8, 10, 14, 18, 20, 24, 28, 32, 38, 52, or 54, and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO: 4, 12, 16, 22, 26, 30, 36, 40, or 56, wherein said antibody binds IL-17F and IL-17A. 
     
     
         19 . The antibody of  claim 18 , wherein said antibody is an IgG isotype. 
     
     
         20 . The antibody of  claim 18 , wherein said antibody is an IgG1 isotype. 
     
     
         21 . An isolated fully human monoclonal antibody, or fragment thereof, wherein said antibody comprises:
 (a) a V H  CDR1 region comprising the amino acid sequence of SEQ ID NO: 85 or 90;   (b) a V H  CDR2 region comprising the amino acid sequence of SEQ ID NO: 88 or 91;   (c) a V H  CDR3 region comprising the amino acid sequence of SEQ ID NO: 89 or 92;   (d) a V L  CDR1 region comprising the amino acid sequence of SEQ ID NO: 101 or 107;   (e) a V L  CDR2 region comprising the amino acid sequence of SEQ ID NO: 102 or 108; and   (f) a V L  CDR3 region comprising the amino acid sequence of SEQ ID NO: 112 or 113,   wherein said antibody binds IL-17F.   
     
     
         22 . The antibody of  claim 21 , wherein said antibody does not bind IL-17A or IL-17A homodimer. 
     
     
         23 . The antibody of  claim 21 , wherein said antibody is an IgG isotype. 
     
     
         24 . The antibody of  claim 21 , wherein said antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 44 and 48. 
     
     
         25 . The antibody of  claim 21 , wherein said antibody further comprises a light chain variable sequence comprising the amino acid sequence of SEQ ID NO: 46 and 50. 
     
     
         26 . A pharmaceutical composition comprising the antibody of  claim 1  and a carrier. 
     
     
         27 . A method of alleviating a symptom of a clinical indication associated rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis chronic obstructive pulmonary disease, or asthma in a subject, the method comprising administering an antagonist of the IL-17A/IL-17F heterodimeric complex to a subject in need thereof in an amount sufficient to alleviate the symptom of the clinical indication associated with rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis chronic obstructive pulmonary disease, or asthma. 
     
     
         28 . The method of  claim 27 , wherein said subject is a human. 
     
     
         29 . The method of  claim 27 , wherein said antagonist is a monoclonal antibody or fragment thereof. 
     
     
         30 . The method of  claim 29 , wherein said monoclonal antibody is the antibody according to  claim 1  or fragment thereof. 
     
     
         31 . A method of alleviating a symptom of an autoimmune disease, inflammatory disorder or cell proliferation disorder, wherein the method comprises administering the antibody according to  claim 1  to a subject in need thereof in an amount sufficient to alleviate the symptom of the autoimmune disease, inflammatory disorder or cell proliferation disorder in the subject. 
     
     
         32 . The method of  claim 31 , wherein said subject is a human.