Antibodies to receptor for advanced glycation end products (rage) and uses thereof

Abstract

The present application relates to antibodies, such as monoclonal antibodies, and in particular CDR grafted, humanized versions thereof, for the treatment and diagnosis of pain and other neuroinflammatory conditions associated with the Receptor for Advanced Glycation End Products (RAGE).

What is claimed is: 
     
         1 . A method for treating pain, comprising the step of administering to a mammal in need thereof an effective amount of a composition comprising an isolated monoclonal antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a human RAGE molecule, said antigen binding domain comprising at least one CDR comprising an amino acid sequence selected from the group consisting of:
 a) the CDR-H3 group of amino acid sequences consisting of SEQ ID NOs: 12 and 20; modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences; and   b) the CDR-L3 group of amino acid sequences consisting of SEQ ID NOs: 16 and 24; and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.   
     
     
         2 . The method according to  claim 1 , wherein the antibody further comprises at least one CDR comprising an amino acid sequence selected from the CDR-H1 group consisting of SEQ ID NOs: 10 and 18; or selected from the CDR-H2 group consisting of SEQ ID NOs: 11, 19; or selected from the CDR-L1 group consisting of SEQ ID NOs: 14 and 22; or selected from the CDR-L2 group consisting of SEQ ID NOs: 15 and 23; and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences. 
     
     
         3 . The method according to  claim 2 , wherein the antibody further comprises at least 3 CDRs which are selected from a variable domain CDR set comprising: 
       
         
           
                 
                 
                 
               
                     
                 
                   VH 11E6 set 
                     
                     
                 
                   VH 11E6 CDR-H1 
                   Residues 31-35 of SEQ ID NO : 9 
                   SEQ ID NO: 10 
                 
                   VH 11E6 CDR-H2 
                   Residues 50-66 of SEQ ID NO : 9 
                   SEQ ID NO: 11 
                 
                   VH 11E6 CDR-H3 
                   Residues 99-109 of SEQ ID NO: 9 
                   SEQ ID NO: 12 
                 
                   VL 11E6 set 
                 
                   VL 11E6 CDR-L1 
                   Residues 24-34 of SEQ ID NO: 13 
                   SEQ ID NO: 14 
                 
                   VL 11E6 CDR-L2 
                   Residues 50-56 of SEQ ID NO: 13 
                   SEQ ID NO: 15 
                 
                   VL 11E6 CDR-L3 
                   Residues 89-97 of SEQ ID NO: 13 
                   SEQ ID NO: 16 
                 
                   VH 4E5 set 
                 
                   VH 4E5 CDR-H1 
                   Residues 31-35 of SEQ ID NO: 17 
                   SEQ ID NO: 18 
                 
                   VH 4E5 CDR-H2 
                   Residues 50-66 of SEQ ID NO: 17 
                   SEQ ID NO: 19 
                 
                   VH 4E5 CDR-H3 
                   Residues 99-109 of SEQ ID NO: 17 
                   SEQ ID NO: 20 
                 
                   VL 4E5 set 
                 
                   VL 4E5 CDR-L1 
                   Residues 24-34 of SEQ ID NO: 21 
                   SEQ ID NO: 22 
                 
                   VL 4E5 CDR-L2 
                   Residues 50-56 of SEQ ID NO: 21 
                   SEQ ID NO: 23 
                 
                   VL 4E5 CDR-L3 
                   Residues 89-97 of SEQ ID NO: 21 
                   SEQ ID NO: 24 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a variable domain set wherein at least one of said 3 CDRs is a modified CDR amino acid sequence having a sequence identity of at least 50% to the parent sequence. 
     
     
         4 . The method according to  claim 1 , wherein the antibody further comprises a human acceptor framework. 
     
     
         5 . The method of  claim 1 , wherein the antibody comprises at least one heavy chain variable domain selected from the group consisting of: SEQ ID NOs: 56 and 57, at least one light chain variable domain selected from the group consisting of: SEQ ID NOs: 58 and 59 or combinations thereof. 
     
     
         6 . The method according to  claim 5 , wherein said binding protein comprises (a) at least one heavy chain framework mutation at a position selected from the group consisting of:
 1, 2, 68, 70, 72, 76, 85, 89 and 95; (b) at least one light chain framework mutation at a position selected from the group consisting of: 11, 13, 43, 49, 58, 70 and 87; or (c) combinations of (a) and (b).   
     
     
         7 . The method of  claim 1 , wherein the antibody comprises (a) at least one framework mutation at a position selected from the group consisting of: 62, 67, 68 and 69; (b) at least one light chain framework mutation at a position selected from the group consisting of: 63, 64, 65 and 66; or (c) combinations of (a) and (b). 
     
     
         8 . The method of  claim 1 , wherein the antibody is selected from the group consisting of antibodies 11E6 and 4E5. 
     
     
         9 . The method of  claim 1 , wherein the composition comprises a formulation, wherein said formulation comprises the antibody of  claim 1  in crystallized form as an ingredient; and at least one polymeric carrier. 
     
     
         10 . The method of  claim 8 , wherein the antibody is 11E6. 
     
     
         11 . The method of  claim 1 , wherein said pain is selected from the group consisting of chronic and acute pain. 
     
     
         12 . The method of  claim 1 , wherein said pain is selected from the group consisting of:
 peripheral or central neuropathic pain, nociceptive pain; and psychogenic pain.   
     
     
         13 . The method of  claim 1 , wherein said pain is nociceptive pain or psychogenic pain. 
     
     
         14 . The method of  claim 1 , wherein said pain is neuropathic pain. 
     
     
         15 . The method of  claim 14 , wherein said neuropathic pain is peripheral or central neuropathic pain. 
     
     
         16 . The method of  claim 1 , wherein said pain is inflammatory pain. 
     
     
         17 . A monoclonal antibody as defined in  claim 1  for use in treating pain.