Targeted binding agents directed to pdgfr-alpha and uses thereof

Abstract

Targeted binding agents directed to the antigen PDGFR-alpha and uses of such agents are disclosed herein. More specifically the invention relates to fully human monoclonal antibodies directed to the antigen PDGFR-alpha and uses of these antibodies. Aspects of the invention also relate to hybridomas or other cell lines expressing such antibodies. The described targeted binding agents and antibodies are useful as diagnostics and for the treatment of diseases associated with the activity and/or overexpression of PDGFR-alpha.

1 . A targeted binding agent that specifically binds to PDGFR-alpha and inhibits the growth of cells that express PDGFR-alpha, wherein the targeted binding agent binds PDGFR-alpha with a KD less than 40 pM. 
     
     
         2 . The targeted binding agent of  claim 1 , wherein said targeted binding agent inhibits the proliferation of MG-63 cells incubated with 3.45 nM PDGF-AA with an IC 50  of less 3.2 nM. 
     
     
         3 . The targeted binding agent of  claim 1 , wherein said targeted binding agent binds to PDGFR-alpha and at a concentration of 2 μg/ml inhibits greater than 90%, or equal to 90%, of tyrosine phosphorylation of PDGFR-alpha on MG-63 cells incubated with 25 ng/ml PDGF-AA. 
     
     
         4 . The targeted binding agent of  claim 1 , wherein said targeted binding agent:
 binds to PDGFR-alpha,   inhibits binding of PDGF-AA, PDGF-AB, PDGF-BB and/or PDGF-CC ligands to PDGFR-alpha;   inhibits downstream cell signaling implicated in cell growths;   does not cross-react with PDGFR-beta receptor; and/or   does not cross react with other Class III receptor tyrosine kinase family members.   
     
     
         5 .- 6 . (canceled) 
     
     
         7 . The targeted binding agent of  claim 1 , wherein said targeted binding agent inhibits tumor growth and metastasis in a mammal. 
     
     
         8 - 19 . (canceled) 
     
     
         20 . The targeted binding agent of  claim 1 , wherein said targeted binding agent comprises a polypeptide comprising the sequence of:
 i. SEQ ID NO.: 2;   ii. SEQ ID NO:2, wherein the sequence comprises any one of the unique combinations of germine and nongermline residues indicated by each row of Table 6;   iii. SEQ ID NO.: 10;   iv. SEQ ID NO:10 wherein the sequence comprises any one of the unique combinations of germine and nongermline residues indicated by each row of Table 8;   v. SEQ ID NO.: 14;   vi. SEQ ID NO:14 wherein the sequence comprises any one of the unique combinations of germline and nongermline residues indicated by each row of Table 10;   vii. SEQ ID NO.: 4;   viii. SEQ ID NO:4 wherein the sequence comprises any one of the unique combinations of germline and nongermline residues indicated by each row of Table 7;   ix. SEQ ID NO.: 12;   x. SEQ ID NO:12 wherein the sequence comprises any one of the unique combinations of germline and nongermline residues indicated by each row of Table 9;   xi. SEQ ID NO.: 16; or   xii. SEQ ID NO:16 wherein the sequence comprises any one of the unique combinations of germline and nongermline residues indicated by each row of Table 11.   
     
     
         21 .- 27 . (canceled) 
     
     
         28 . A targeted binding agent comprising an amino acid sequence comprising
 a CDR3 sequence as shown in Table 12 or Table 13;   a CDR3 sequence as shown in Table 12 and a CDR3 sequence as shown in Table 13;   a CDR1, CDR2 and CDR3 sequence as shown in Table 12;   a CDR1, CDR2 and CDR3 sequence as shown in Table 13; or   a CDR1, CDR2 and CDR3 sequence as shown in Table 12 and a CDR1, CDR2 and CDR3 sequence as shown in Table 13.   
     
     
         29 . A targeted binding agent according to  claim 20  wherein said targeted binding agent is:
 an antibody;   a monoclonal antibody;   a fully human monoclonal antibody;   a binding fragment of a fully human monoclonal antibody; or   a binding fragment of a fully human monoclonal antibody selected from the group consisting of Fab, Fab′, F(ab′)2, Fv and dAb.   
     
     
         30 . A targeted binding agent, wherein said targeted binding agent is:
 i any one of the monoclonal antibodies as shown in Table 1;   ii monoclonal antibody 2.175.3;   iii. monoclonal antibody 2.175.3 variant A;   iv. monoclonal antibody 2.449.1.3;   v. monoclonal antibody 2.449.1.3 variant A;   vi monoclonal antibody 2.449.1.3 wherein the antibody comprises a light chain polypeptide comprising the sequence of SEQ ID NO:12, wherein the sequence comprises the unique combination of germline and non-germline residues indicated by row 3968 of Table 9; or   vii. monoclonal antibody 2.998.2.   
     
     
         31 . A targeted binding agent, wherein said targeted binding agent comprises an antibody which comprises variants or derivatives of the monoclonal antibody of  claim 20  or  claim 28 , and/or has at least 80% amino acid sequence identity with the monoclonal antibody of  claim 20  or  claim 28 . 
     
     
         32 . A nucleic acid molecule encoding the targeted binding agent of any one of  claims 20  or  28 . 
     
     
         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 treating a neoplastic disease in an mammal, comprising:
 selecting an animal in need of treatment for a neoplastic disease; and   administering to said animal a therapeutically effective dose of the targeted binding agent of any one of  claims 1 ,  20 , or  28 .   
     
     
         36 . The method of  claim 35 , wherein said animal is human. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claims 35 , wherein said neoplastic disease 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, epidermoid carcinoma and gastrointestinal stromal tumor (GIST). 
     
     
         39 . A method of treating a non-neoplastic disease, comprising:
 selecting an animal in need of treatment for a non-neoplastic disease; and   administering to said animal a therapeutically effective dose of the targeted binding agent of any one of  claims 1 ,  20 , or  28 .   
     
     
         40 . The method of  claim 39 , wherein said animal is human. 
     
     
         41 . The method of  claim 40 , wherein said targeted binding agent is a fully human monoclonal antibody. 
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 39 , wherein the non-neoplastic disease is selected from fibrotic or immune system diseases. 
     
     
         44 .- 50 . (canceled) 
     
     
         51 . A composition comprising the targeted binding agent of any of  claims 1 ,  20 , or  28 . 
     
     
         52 . The composition of  claim 51 , in association with a pharmaceutically acceptable carrier. 
     
     
         53 . A targeted binding agent which competes for binding to PDGFR-alpha with any one of the targeted binding agents of claims; and or binds to the same epitope on PDGFR-alpha as any one of the targeted binding agents of  claims 1 ,  20  or  28 . 
     
     
         53 . A method of producing an antibody by culturing the host cell of  claim 34  under conditions wherein a nucleic acid molecule is expressed to produce the antibody, followed by recovering the antibody.