Compositions and methods for binding lysophosphatidic acid

Abstract

Compositions and methods for making and using anti-LPA agents, for example, monoclonal antibodies, are described. Variable domain and complementarity determining region amino acid sequences of several monoclonal antibodies against LPA are disclosed, as is a consensus anti-LPA monoclonal antibody variable domain sequence.

What is claimed is: 
     
         1 . A method of treating or preventing a disease or disorder associated with aberrant levels of lysophosphatidic acid (LPA), comprising administering to a subject in need of such treatment an antibody or fragment thereof that binds LPA under physiological conditions in an amount effective to reduce in vivo the effective concentration of LPA, thereby effecting treatment or prevention of the disease or disorder,
 (A) wherein the disease or disorder is selected from the group consisting of a hyperproliferative disease, including cancer; an immune-related disease, including an autoimmune disease, allograft rejection and graft-vs-host disease; obesity; type 2 diabetes; an ocular disease, including macular degeneration; pain; a disease associated with aberrant angiogenesis or neovascularization; apoptosis; fibrogenesis or fibrosis, including scleroderma, pulmonary fibrosis, renal fibrosis, skin fibrosis, cardiac fibrosis, and hepatic fibrosis; wound repair and healing; and spider bite, and   (B) wherein the antibody or fragment thereof that binds lysophosphatidic acid (LPA) under physiological conditions comprises at least one heavy chain variable domain and at least one light chain variable domain, wherein   (i) each heavy chain variable domain comprises first, second, and third heavy chain complementarity determining regions (CDRs), wherein the first heavy chain CDR comprises an amino acid sequence having at least about 65% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 56, 62, 68, 89 and 95, the second heavy chain CDR comprises an amino acid sequence having at least about 65% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 57, 69, 78 and 90, and the third heavy chain CDR comprises an amino acid sequence having at least about 65% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 58, 70, 79, 82 and 91; and   (ii) each light chain variable domain comprises first, second, and third light chain CDRs, wherein the first light chain CDR comprises an amino acid sequence having at least about 65% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 59, 71, 80, and 92, the second light chain CDR comprises an amino acid sequence having at least about 65% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO; 60, 72 and 93, and the third light chain CDR comprises an amino acid sequence having at least about 65% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 61 and 94.   
     
     
         2 . The method of  claim 1  wherein the antibody or fragment thereof is selected from the group consisting of a chimeric antibody, a humanized antibody, a full-length antibody or an affinity matured antibody, or an LPA-binding fragment of one of the foregoing. 
     
     
         3 . The method of  claim 1  wherein the antibody or fragment thereof that binds lysophosphatidic acid (LPA) under physiological conditions comprises two heavy chain variable domains and two light chain variable domains. 
     
     
         4 . The method of claim  1 (B) wherein
 (i) each heavy chain variable domain comprises first, second, and third heavy chain complementarity determining regions (CDRs), wherein the first heavy chain CDR comprises an amino acid selected from the group consisting of SEQ ID NO: 56, 62, 68, 89 and 95, the second heavy chain CDR comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 57, 69, 78 and 90, and the third heavy chain CDR comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 58, 70, 79, 82 and 91; and,   (ii) each light chain variable domain comprises first, second, and third light chain CDRs, wherein the first light chain CDR comprises an amino sequence selected from the group consisting of SEQ ID NO: 59, 71, 80, and 92, the second light chain CDR comprises an amino acid sequence selected from the group consisting of SEQ ID NO; 60, 72 and 93, and the third light chain CDR comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61 and 94.   
     
     
         5 . The method of  claim 4  wherein each heavy chain independently comprises an amino acid sequence having at least about 65% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 116, 118, 120, 122 and 124 and each light chain independently comprises an amino acid sequence having at least about 65% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 117, 119, 121, 123 and 125. 
     
     
         6 . The method of  claim 5  wherein said heavy chains and said light chains are independently derived from two or more different hybridoma cells. 
     
     
         7 . The method of claim wherein each heavy chain independently comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 116, 118, 120, 122 and 124 and each light chain independently comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 117, 119, 121, 123 and 125. 
     
     
         8 . The method of  claim 1  wherein the antibody or fragment thereof is conjugated to a moiety selected from the group consisting of a polymer, a radionuclide, a chemotherapeutic agent, and a detection agent. 
     
     
         9 . The method of  claim 1  wherein the antibody or fragment thereof comprises a heavy chain variable domain sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 126) 
                 
                 
               
                   QVXLQQSGXELVRPGTSVK*SCXASGXXFXNYLIEW#KQRPGQGLEWIGL 
                 
                     
                 
                   IXPX&XYXNYNENFKGKATLTAD@SSSTAYMXLSSLTSEDSAVYFCARRF 
                 
                     
                 
                   XYYGSXXYFDYWGQGTTLTVSS, 
                 
                   wherein * is V or L, # is V or I, @ is K or 
                 
                   R and & is T or S, 
                 
             
                
               
            
             
                
                
                
                
                
                
                
               
            
           
         
         or a light chain variable domain sequence: 
       
       
         
           
                 
               
                   (SEQ ID NO: 127) 
                 
                 
               
                   DVVMTQTPLSLPVSLGDQASISCXSXQSL*XXNGNTYLHWYLQKPGQSPK 
                 
                     
                 
                   LLIXKVSNXFSGVPDRFSGSGXGTDFTLKISRVEAEDLGXYFCSQSTHF 
                 
                     
                 
                   PFTFGTGTKLEIK, 
                 
                   wherein * is V or L. 
                 
             
                
               
            
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         10 . The method of  claim 9  wherein the antibody or fragment thereof comprises two heavy chains and two light chains, wherein each heavy chain comprises a variable domain having the sequence 
       
         
           
                 
               
                   (SEQ ID NO: 126) 
                 
                 
               
                   QVXLQQSGXELVRPGTSVK*SCXASGXXFXNYLIEW#KQRPGQGLEWIG 
                 
                     
                 
                   LIXPX&XYXNYNENFKGKATLTAD@SSSTAYMXLSSLTSEDSAVYFCAR 
                 
                     
                 
                   RFXYYGSXXYFDYWGQGTTLTVSS, 
                 
                   wherein * is V or L, # is V or I, @ is K or 
                 
                   R and & is T or S; 
                 
             
                
               
            
             
                
                
                
                
                
                
                
               
            
           
         
         and each light chain comprises a variable domain having the sequence: 
       
       
         
           
                 
               
                   (SEQ ID NO: 127) 
                 
                 
               
                   DVVMTQTPLSLPVSLGDQASISCXSXQSL*XXNGNTYLHWYLQKPGQSP 
                 
                     
                 
                   KLLIXKVSNXFSGVPDRFSGSGXGTDFTLKISRVEAEDLGXYFCSQSTH 
                 
                     
                 
                   FPFTFGTGTKLEIK, 
                 
                   wherein * is V or L.