Anti-RANTES Antibodies

Abstract

The invention relates to fully human monoclonal antibodies, and fragments thereof, that bind to the chemokine Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES, CCL5), thereby modulating the interaction between RANTES and one of more of its receptors, such as, e.g., CCR1, CCR3, CCR4 and CCR5, and/or modulating the biological activities of RANTES. The invention also relates to the use of these or any anti-RANTES antibodies in the prevention or treatment of immune-related disorders and in the amelioration of one or more symptoms associated with an immune-related disorder.

What is claimed is: 
     
         1 . An isolated antagonist molecule of human RANTES, wherein said antagonist molecule binds a human RANTES polypeptide that comprises at least residues acid residues 16-18 of SEQ ID NO: 170 and reduces a biological activity of RANTES activity upon interaction between said antagonist and said human RANTES polypeptide. 
     
     
         2 . The antagonist molecule of  claim 1 , wherein said antagonist molecule does not bind a human RANTES polypeptide that lacks amino acid residues 16-18 of SEQ ID NO: 170. 
     
     
         3 . The antagonist molecule of  claim 1 , wherein said antagonist molecule is selected from a small molecule inhibitor; a polypeptide, a peptide, and a nucleic acid-based antagonist. 
     
     
         4 . The antagonist molecule of  claim 1 , wherein said antagonists is an isolated monoclonal anti-human RANTES antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof binds to an epitope on a mature human RANTES polypeptide, said epitope comprising amino acid residues 16-18 of SEQ ID NO: 170. 
     
     
         5 . The antagonist molecule of  claim 4 , wherein said monoclonal antibody is a fully human monoclonal anti-human RANTES antibody or antigen-binding fragment thereof. 
     
     
         6 . The antagonist molecule of  claim 5 , wherein said antibody is an IgG1 isotype. 
     
     
         7 . An isolated fully human monoclonal anti-human RANTES antibody or fragment thereof, wherein said antibody comprises:
 (a) a V H  CDR1 region comprising the amino acid sequence of SEQ ID NO: 8, 28, 44, 74, 90, 106, 122, 138, 154, or 222;   (b) a V H  CDR2 region comprising the amino acid sequence of SEQ ID NO: 9, 29, 45, 75, 91, 107, 123, 139, 155, 207, 223, 239, or 255;   (c) a V H  CDR3 region comprising the amino acid sequence of SEQ ID NO: 10, 20, 30, 46, 50, 54, 58, 64, 76, 92, 108, 124, 140, 156, 169, 188, 208, 224, or 240,   (d) a V L  CDR1 region comprising the amino acid sequence of SEQ ID NO: 14, 34, 77, 96, 112, 128, 144, 160, 176, 190, 192, 212, 228, or 244;   (e) a V L  CDR2 region comprising the amino acid sequence of SEQ ID NO: 15, 35, 81, 97, 113, 129, 145, 161, 177, 191, 193, 213, 229, or 245; and   (f) a V L  CDR3 region comprising the amino acid sequence of SEQ ID NO: 16, 36, 66, 82, 98, 114, 130, 146, 162, 178, 194, 214, 230, 235 or 246,   wherein said antibody binds RANTES.   
     
     
         8 . The antibody of  claim 7 , wherein said antibody comprises a combination of a V H  CDR1 region, a V H  CDR2 region, a V H  CDR3 region, a V L  CDR1 region, a V L  CDR2 region, and a V L  CDR1 region selected from the group consisting of:
 (a) a V H  CDR1 region comprising the amino acid sequence of SEQ ID NO: 8; a V H  CDR2 region comprising the amino acid sequence of SEQ ID NO:9, a V H  CDR3 region comprising the amino acid sequence of SEQ ID NO:10; a V L  CDR1 region comprising the amino acid sequence of SEQ ID NO: 14; a V L  CDR2 region comprising the amino acid sequence of SEQ ID NO: 15; and a V L  CDR3 region comprising an amino acid sequence of SEQ ID NO:16;   (b) a V H  CDR1 region comprising the amino acid sequence of SEQ ID NO: 8; a V H  CDR2 region comprising the amino acid sequence of SEQ ID NO:9, a V H  CDR3 region comprising the amino acid sequence of SEQ ID NO:20; a V L  CDR1 region comprising the amino acid sequence of SEQ ID NO: 14; a V L  CDR2 region comprising the amino acid sequence of SEQ ID NO: 15; and a V L  CDR3 region comprising an amino acid sequence of SEQ ID NO:16; and   (c) a V H  CDR1 region comprising the amino acid sequence of SEQ ID NO: 28; a V H  CDR2 region comprising the amino acid sequence of SEQ ID NO:29, a V H  CDR3 region comprising the amino acid sequence of SEQ ID NO:30; a V L  CDR1 region comprising the amino acid sequence of SEQ ID NO: 34; a V L  CDR2 region comprising the amino acid sequence of SEQ ID NO:35; and a V L  CDR3 region comprising an amino acid sequence of SEQ ID NO:36.   
     
     
         9 . The antibody of  claim 7 , wherein said antibody is an IgG isotype. 
     
     
         10 . The antibody of  claim 7 , wherein said antibody is an IgG1 isotype. 
     
     
         11 . The antibody of  claim 7 , wherein said antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2, 18, 22, 38, 48, 52, 56, 60, 68, 84, 100, 116, 132, 148, 164, 180, 200, 216, 232, or 248 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO: 4, 24, 40, 62, 70, 86, 102, 118, 134, 150, 166, 182, 196, 202, 218, 234, or 250. 
     
     
         12 . The antibody of  claim 11 , wherein said antibody is an IgG isotype. 
     
     
         13 . The antibody of  claim 11 , wherein said antibody comprises a combination of a heavy chain variable sequence and a light chain variable sequence selected from the group consisting of:
 (a) a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:4;   (b) a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:18 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:4; and   (c) a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:24.   
     
     
         14 . The antibody of  claim 13 , wherein said antibody comprises a combination of a heavy chain sequence and a light chain variable sequence selected from the group consisting of:
 (a) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 167 and a light chain sequence comprising the amino acid sequence of SEQ ID NO: 168;   (b) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO:238 and a light chain sequence comprising the amino acid sequence of SEQ ID NO:254; and   (c) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO:186 and a light chain sequence comprising the amino acid sequence of SEQ ID NO:187.   
     
     
         15 . The antibody of  claim 13 , wherein said antibody is an IgG isotype. 
     
     
         16 . The antibody of  claim 15 , wherein said antibody is an IgG1 isotype. 
     
     
         17 . A pharmaceutical composition comprising the antibody of  claim 1  and a carrier. 
     
     
         18 . An isolated antibody that binds human RANTES when human RANTES is bound to a glycosaminoglycan (GAG), wherein said antibody comprises:
 (a) a V H  CDR1 region comprising the amino acid sequence of SEQ ID NO: 8, 28, 44, 90, 106, 122 or 154;   (b) a V H  CDR2 region comprising the amino acid sequence of SEQ ID NO: 9, 29, 45, 91, 107, 123, 155, or 207;   (c) a V H  CDR3 region comprising the amino acid sequence of SEQ ID NO: 10, 20, 30, 64, 92, 124, 156, 188, or 208,   (d) a V L  CDR1 region comprising the amino acid sequence of SEQ ID NO: 14, 34, 96, 128, 160, 176, 192, or 212;   (e) a V L  CDR2 region comprising the amino acid sequence of SEQ ID NO: 15, 35, 97, 129, 161, 177, 193, or 213; and   (f) a V L  CDR3 region comprising the amino acid sequence of SEQ ID NO: 16, 36, 98, 130, 162, 178, 194, or 214.   wherein said antibody binds RANTES in the context of GAG.   
     
     
         19 . The antibody of  claim 18 , wherein said antibody is a monoclonal antibody or an antigen-binding fragment thereof. 
     
     
         20 . The antibody of  claim 18 , wherein said antibody is a fully human monoclonal antibody or an antigen-binding fragment thereof. 
     
     
         21 . The antibody of  claim 18 , wherein said antibody is an IgG isotype. 
     
     
         22 . The antibody of  claim 18 , wherein said antibody is an IgG1 isotype. 
     
     
         23 . A method of alleviating a symptom of a clinical indication associated with ischemia or reperfusion injury in a subject, the method comprising administering the antagonist of  claim 1  to a subject in need thereof in an amount sufficient to alleviate the symptom of the clinical indication associated with ischemia or reperfusion injury in the subject. 
     
     
         24 . The method of  claim 23 , wherein said subject is a human. 
     
     
         25 . The method of  claim 23 , wherein said antagonist is a monoclonal antibody or an antigen-binding fragment thereof. 
     
     
         26 . The method of  claim 23 , wherein said antagonist is the antibody of  claim 7 . 
     
     
         27 . The method of claim  31 , wherein said antagonist is a mutated RANTES polypeptide that modulates an activity of RANTES selected from the ability of RANTES to bind to a receptor selected from CCR1, CCR3, CCR4, and CCR5, the ability of RANTES to bind a glycosaminoglycan and the ability of RANTES to form oligomers. 
     
     
         28 . A method of alleviating a symptom of an autoimmune disease or inflammatory disorder, the method comprising administering the antibody of  claim 7  to a subject in need thereof in an amount sufficient to alleviate the symptom of the autoimmune disease or inflammatory disorder in the subject. 
     
     
         29 . The method of  claim 28 , wherein said subject is a human.