Antibodies Directed to AlphaVBeta6 and Uses Thereof

Abstract

Targeted binding agents, such antibodies directed to the antigen αVβ6 and uses of such agents are described. In particular, fully human monoclonal antibodies directed to the antigen αVβ6 are disclosed. Nucleotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions and/or complementarity determining regions (CDR's), specifically from FR1 through FR4 or CDR1 through CDR3 are disclosed. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies are also disclosed.

1 . A targeted binding agent that specifically binds to αVβ6 and inhibits binding of ligands to αVβ6.  
     
     
         2 . The targeted binding agent of  claim 1 , wherein said targeted binding agent inhibits greater than 99% of TGFβ-LAP mediated adhesion of HT29 cells.  
     
     
         3 . The targeted binding agent of  claim 1 , wherein said targeted binding agent inhibits TGFβ-LAP mediated adhesion of HT29 cells with an IC 50  of less than 0.070 μg/ml.  
     
     
         4 . The targeted binding agent of  claim 1 , wherein said targeted binding agent binds αVβ6 with a Kd of less than 35 nanomolar (nM).  
     
     
         5 . The targeted binding agent of  claim 1 , wherein said targeted binding agent binds αVβ6 with a Kd of less than 25 nanomolar (nM).  
     
     
         6 . The targeted binding agent of  claim 1 , wherein said targeted binding agent binds αVβ6 with a Kd of less than 10 nanomolar (nM).  
     
     
         7 . The targeted binding agent, of  claim 1 , wherein said targeted binding agent binds αVβ6 with a Kd of less than 60 picomolar (pM).  
     
     
         8 . The targeted binding agent of  claim 1 , wherein said targeted binding agent is a monoclonal antibody.  
     
     
         9 . The targeted binding agent of  claim 8 , wherein said targeted binding agent is a fully human monoclonal antibody.  
     
     
         10 . The targeted binding agent of  claim 9 , wherein said targeted binding agent is sc 264 RAD, sc 264 RAD/ADY, sc 188 SDM, sc 133, sc 133 TMT, sc 133 WDS, sc 133 TMT/WDS, sc 188, sc 254, sc 264 or sc 298.  
     
     
         11 . The targeted binding agent of  claim 11 , wherein said binding agent comprises at least the VH CDR3 having amino acids 98-102 of SEQ ID NO.: 14.  
     
     
         12 . The targeted binding agent of  claim 1 , wherein said binding agent comprises at least the VH CDR3 having amino acids 99-113 of SEQ ID NO.: 22.  
     
     
         13 . The targeted binding agent of  claim 1 , wherein said binding agent comprises at least the VH CDR3 having amino acids 99-117 of SEQ ID NO.: 26.  
     
     
         14 . The targeted binding agent of  claim 1 , wherein said binding agent comprises at least the VH CDR3 having amino acids 99-114 of SEQ ID NO.: 30.  
     
     
         15 . The targeted binding agent of  claim 1 , wherein said binding agent comprises at least the VH CDR3 having amino acids 97-113 of SEQ ID NO.: 38.  
     
     
         16 . The targeted binding agent of  claim 1 , wherein said binding agent comprises a heavy chain polypeptide having the sequence of SEQ ID NO.: 14.  
     
     
         17 . The targeted binding agent of  claim 1 , wherein said binding agent comprises a heavy chain polypeptide having the sequence of SEQ ID NO.: 22.  
     
     
         18 . The targeted binding agent of  claim 1 , wherein said binding agent comprises a heavy chain polypeptide having the sequence of SEQ ID NO.: 26.  
     
     
         19 . The targeted binding agent of  claim 1 , wherein said binding agent comprises a heavy chain polypeptide having the sequence of SEQ ID NO.: 30.  
     
     
         20 . The targeted binding agent of  claim 1 , wherein said binding agent comprises a heavy chain polypeptide having the sequence of SEQ ID NO.: 38.  
     
     
         21 . The targeted binding agent of  claim 1 , wherein said binding agent comprises a heavy chain polypeptide having the sequence of SEQ ID NO.: 71.  
     
     
         22 . The targeted binding agent of  claim 1 , wherein said binding agent comprises a heavy chain polypeptide having the sequence of SEQ ID NO.: 75.  
     
     
         23 . An isolated antibody that binds αVβ6, wherein the antibody comprises: 
 a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences; and    a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein    the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NO.: 14, SEQ ID NO.: 22, SEQ ID NO.: 26, SEQ ID NO.: 30 or SEQ ID NO.: 38, SEQ ID NO:71, SEQ ID NO: 76, SEQ ID NO: 79 and conservative sequence modifications thereof, and the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: SEQ ID NO.: 16, SEQ ID NO.: 24, SEQ ID NO.: 28, SEQ ID NO.: 32 or SEQ ID NO.: 40, SEQ ID NO:85, SEQ ID NO: 93, and conservative sequence modifications thereof.    
     
     
         24 . An isolated fully human antibody that binds αVβ6, wherein the antibody comprises: 
 a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences; and    a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein    the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NO.: 14, SEQ ID NO.: 22, SEQ ID NO.: 26, SEQ ID NO.: 30 or SEQ ID NO.: 38, SEQ ID NO:71, SEQ ID NO: 76, SEQ ID NO: 79 and conservative sequence modifications thereof, and the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: SEQ ID NO.: 16, SEQ ID NO.: 24, SEQ ID NO.: 28, SEQ ID NO.: 32 or SEQ ID NO.: 40, SEQ ID NO:85, SEQ ID NO: 93, and conservative sequence modifications thereof.    
     
     
         25 . An isolated antibody fragment that binds αVβ6, wherein the antibody fragment comprises: 
 a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences; and    a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein    the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NO.: 14, SEQ ID NO.: 22, SEQ ID NO.: 26, SEQ ID NO.: 30 or SEQ ID NO.: 38, SEQ ID NO:71, SEQ ID NO: 76, SEQ ID NO: 79 and conservative sequence modifications thereof, and    the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: SEQ ID NO.: 16, SEQ ID NO.: 24, SEQ ID NO.: 28, SEQ ID NO.: 32 or SEQ ID NO.: 40, SEQ ID NO:85, SEQ ID NO: 93, and conservative sequence modifications thereof.    
     
     
         26 . The targeted binding agent of  claim 1 , in association with a pharmaceutically acceptable carrier.  
     
     
         27 . The targeted binding agent of  claim 1 , wherein said targeted binding agent is a fully human isolated binding fragment of an anti-αVβ6 antibody.  
     
     
         28 . A nucleic acid molecule encoding the targeted binding agent of  claim 1 .  
     
     
         29 . A vector comprising the nucleic acid molecule of  claim 26 .  
     
     
         30 . A host cell comprising the vector of  claim 27 .  
     
     
         31 . A method of producing a targeted binding agent, comprising culturing a host cell of  claim 30 .  
     
     
         32 . A nucleic acid molecule encoding an antibody of  claim 23 .  
     
     
         33 . A vector comprising the nucleic acid molecule of  claim 32 .  
     
     
         34 . A host cell comprising the vector of  claim 33 .  
     
     
         35 . A method of producing an antibody, comprising culturing a host cell of  claim 34 .  
     
     
         36 . A nucleic acid molecule encoding a fully human antibody of  claim 24 .  
     
     
         37 . A vector comprising the nucleic acid molecule of  claim 36 .  
     
     
         38 . A host cell comprising the vector of  claim 37 .  
     
     
         39 . A method of producing a fully human antibody, comprising culturing a host cell of  claim 38 .  
     
     
         40 . A nucleic acid molecule encoding an antibody fragment of  claim 25 .  
     
     
         41 . A vector comprising the nucleic acid molecule of  claim 40 .  
     
     
         42 . A host cell comprising the vector of  claim 41 .  
     
     
         43 . A method of producing an antibody fragment, comprising culturing a host cell of  claim 42 .  
     
     
         44 . A method of treating a malignant tumor in an animal, comprising administering to said animal in need thereof a therapeutically effective dose of the targeted binding agent of  claim 1 .  
     
     
         45 . The method of  claim 29 , wherein said animal is human.  
     
     
         46 . The method of  claim 29 , wherein said targeted binding agent is the monoclonal antibody sc 264 RAD, sc 264 RAD/ADY, sc 188 SDM, sc 133, sc 133 TMT, sc 133 WDS, sc 133 TMT/WDS, sc 188, sc 254, sc 264 or sc 298.  
     
     
         47 . The method of  claim 29 , wherein said malignant tumor is selected from the group consisting of: melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, thyroid tumor, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, colon cancer, pancreatic cancer, esophageal carcinoma, head and neck cancers, mesothelioma, sarcomas, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies and epidermoid carcinoma.  
     
     
         48 . A method of treating inflammation, comprising administering to an animal in need thereof a therapeutically effective dose of the targeted binding agent of  claim 1 .  
     
     
         49 . The method of  claim 33 , wherein said animal is human.  
     
     
         50 . The method of  claim 33 , wherein said targeted binding agent is a fully human monoclonal antibody.  
     
     
         51 . The method of  claim 33 , wherein the targeted binding agent binds to αVβ6.  
     
     
         52 . A method of inhibiting the interaction of αVβ6 with it's ligand, comprising contacting αVβ6 with a targeted binding agent of  claim 1 .  
     
     
         53 . A method of treating a malignant tumor in an animal, comprising administering to said animal in need thereof a therapeutically effective dose of an antibody of  claim 23 .  
     
     
         54 . A method of treating inflammation, comprising administering to an animal in need thereof a therapeutically effective dose of an antibody of  claim 23 .  
     
     
         55 . A method of treating a malignant tumor in an animal, comprising administering to an animal in need thereof a therapeutically effective dose of a fully human antibody of  claim 24 .  
     
     
         56 . A method of treating inflammation, comprising administering to an animal in need thereof a therapeutically effective dose of a fully human antibody of  claim 24 .  
     
     
         57 . A method of treating a malignant tumor in an animal, comprising administering to an animal in need thereof a therapeutically effective dose of an antibody fragment of  claim 25 .  
     
     
         58 . A method of treating inflammation, comprising administering to an animal in need thereof a therapeutically effective dose of an antibody fragment of  claim 25 .  
     
     
         59 . A conjugate comprising a targeted binding agent of  claim 1 .  
     
     
         60 . A conjugate comprising an antibody of  claim 23 .  
     
     
         61 . A conjugate comprising a fully human antibody of  claim 24 .  
     
     
         62 . A conjugate comprising an antibody fragment of  claim 25.