TARGETED BINDING AGENTS DIRECTED TO a5ß1 AND USES THEREOF

Abstract

The invention relates to targeted binding agents against α5β1 and uses of such agents. More specifically, the invention relates to fully human monoclonal antibodies directed to α5β1. The described targeted binding agents are useful in the treatment of diseases associated with the activity and/or overproduction of α5β1 and as diagnostics.

1 . A targeted binding agent that specifically binds to α5β1 integrin, wherein said targeted binding agent contains an RGD tripeptide in any one of the CDRs. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . A targeted binding agent of  claim 1 , wherein said targeted binding agent binds α5β1 integrin with a Kd of less than 250 picomolar. 
     
     
         5 . A targeted binding agent of  claim 1 , wherein said targeted binding agent inhibits binding of fibronectin, fibrin, adhesion molecule L1-CAM, Tie-2 and/or Flt1 ligands to α5β1 integrin. 
     
     
         6 . A targeted binding agent of  claim 1  wherein said targeted binding agent comprises heavy and light chain variable regions according to Table 10 and 11. 
     
     
         7 . A targeted binding agent  claim 1  wherein said targeted binding agent is MAb 2H12 or 2H12 Variant 1. 
     
     
         8 . A targeted binding agent of  claim 1 , wherein said targeted binding agent comprises a polypeptide comprising the sequence of SEQ ID NO.: 12. 
     
     
         9 . A targeted binding agent of  claim 1 , wherein said targeted binding agent comprises a polypeptide comprising the sequence of SEQ ID NO.: 10. 
     
     
         10 . A targeted binding agent of  claim 1 , wherein said targeted binding agent comprises a polypeptide comprising the sequence of SEQ ID NO.: 20. 
     
     
         11 . A targeted binding agent which competes for binding to α5β1 integrin with the targeted binding agent of  claim 1 . 
     
     
         12 . A targeted binding agent comprising an amino acid sequence comprising:
 a) a CDR3 sequence as shown in Table 10 or 11;   b) a CDR3 sequence as shown in Table 10 and a CDR3 sequence as shown in Table 11;   c) a CDR1, CDR2, and CDR3 sequence as shown in Table 10; or   d) a CDR1, a CDR2 and a CDR3 sequence as shown in Table 11; or   e) a CDR1, a CDR2 and a CDR3 sequence as shown in Table 10 and a CDR1, a CDR2 and a CDR3 sequence as shown in Table 11; or   f) a CDR1, CDR2 and CDR3 sequence of McAb. 2H12 as shown in Table 10 and a CDR1, CDR2, CDR3 sequence of McAb. 2H12 as shown in Table 11.   g) a CDR1, CDR2 and CDR3 sequence of McAb. 2H12 Variant 1 as shown in Table 10 and a CDR1, CDR2, CDR3 sequence of McAb. 2H12 Variant 1 as shown in Table 11.   
     
     
         13 . A targeted binding agent comprising a set of CDRs: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, wherein the set of CDRs has 10 or fewer amino acid substitutions from a set of CDRs in which:
 HCDR1 is amino acid sequence SEQ ID NO: 13;   HCDR2 is amino acid sequence SEQ ID NO: 14;   HCDR3 is amino acid sequence SEQ ID NO: 15;   LCDR1 is amino acid sequence SEQ ID NO: 16;   LCDR2 is amino acid sequence SEQ ID NO: 17; and   LCDR3 is amino acid sequence SEQ ID NO: 18.   
     
     
         14 . A targeted binding agent according to  claim 13 , comprising one or two substitutions in the set of CDRs. 
     
     
         15 . A targeted binding agent of  claim 12  wherein said targeted binding agent is a monoclonal antibody. 
     
     
         16 . A targeted binding agent of  claim 15 , wherein said targeted binding agent is a fragment of a monoclonal antibody selected from the group consisting of Fab, Fab′, F(ab′) 2 , Fv, ScFv, ScFvFc or dAb. 
     
     
         17 . (canceled) 
     
     
         18 . A nucleic acid encoding a targeted binding agent according to  claim 12 . 
     
     
         19 . A vector comprising the nucleic acid molecule of  claim 18 . 
     
     
         20 . A host cell comprising the vector of  claim 19 . 
     
     
         21 . A method of producing an antibody comprising culturing the host cell of  claim 20  and recovering the antibody from the cell culture. 
     
     
         22 . A method of treating a neoplastic disease in a mammal comprising:
 selecting an animal in need of treatment for a neoplastic disease; and administering to said animal a therapeutically effective dose of a targeted binding agent of  claim 12 .   
     
     
         23 . The method of  claim 22 , wherein said neoplastic disease is selected from the group consisting of: melanoma, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular carcinoma, thyroid tumor, gastric 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, small bowel adenocarcinoma, pediatric malignancies, epidermoid carcinoma and gastrointestinal stromal tumour. 
     
     
         24 - 28 . (canceled) 
     
     
         29 . The targeted binding agent of  claim 12  in association with a pharmaceutically acceptable carrier. 
     
     
         30 . The targeted binding agent of  claim 12  in combination with an antagonist of vascular endothelial growth factor.