Anti-vegfr antibody and uses thereof

Abstract

The present invention relates to an antibody or antigen-binding fragment thereof that bind human vascular endothelial growth factor receptor 2 (VEGFR-2). The present invention also relates to a method for inhibiting VEGFR-2-mediated signaling in a subject in need, a method for treating diseases and/or disorders caused by or related to VEGFR-2 activity and/or signaling in a subject afflicted with the diseases and disorders, a method for treating tumor in a subject afflicted with the tumor, a method for inhibiting cell proliferation of endothelial cells in a subject in need, and a method for detecting human vascular endothelial growth factor receptor in a sample.

What is claimed is: 
     
         1 . An antibody or antigen-binding fragment thereof that specifically binds to an epitope in human vascular endothelial growth factor receptor 2 (VEGFR-2) or a fragment thereof; wherein the human vascular endothelial growth factor receptor 2 has the amino acid sequence of SEQ ID NO: 1, and the epitope comprises:
 the leucine residue at position 606, the aspartic acid residue at position 607, the arginine residue at position 647, the lysine residue at position 648, and the threonine residue at position 649 of SEQ ID NO: 1; or   the serine residue at position 711, the valine residue at position 714, and the arginine residues at positions 725 and 726 of SEQ ID NO: 1.   
     
     
         2 . The antibody or antigen-binding fragment thereof according to  claim 1 , which is a mammalian antibody. 
     
     
         3 . The antibody or antigen-binding fragment thereof according to  claim 1 , which comprises complementarity determining regions (CDRs) of a heavy chain variable region and complementarity determining regions of a light chain variable region, wherein the complementarity determining regions of the heavy chain variable region comprises CDRH1, CDRH2 and CDRH3 regions, and the complementarity determining regions of the light chain variable region comprises CDRL1, CDRL2 and CDRL3 regions, and the CDRH1 region comprises the amino acid sequence of SEQ ID NO: 4 or a substantially similar sequence thereof; the CDRH2 region comprises the amino acid sequence of SEQ ID NO: 5 or a substantially similar sequence thereof; the CDRH3 region comprises the amino acid sequence of SEQ ID NO: 6 or a substantially similar sequence thereof; the CDRL1 region comprises the amino acid sequence of SEQ ID NO: 7 or a substantially similar sequence thereof; the CDRL2 region comprises the amino acid sequence of SEQ ID NO: 8 or a substantially similar sequence thereof; and the CDRL3 region comprises the amino acid sequence of SEQ ID NO: 9 or a substantially similar sequence thereof. 
     
     
         4 . The antibody or antigen-binding fragment thereof according to  claim 1 , which comprises complementarity determining regions of a heavy chain variable region and complementarity determining regions of a light chain variable region, wherein the complementarity determining regions of the heavy chain variable region comprises CDRH1, CDRH2 and CDRH3 regions, and the complementarity determining regions of the light chain variable region comprises CDRL1, CDRL2 and CDRL3 regions, and the CDRH1 region comprises the amino acid sequence of SEQ ID NO: 10 or a substantially similar sequence thereof; the CDRH2 region comprises the amino acid sequence of SEQ ID NO: 11 or a substantially similar sequence thereof; the CDRH3 region comprises the amino acid sequence of SEQ ID NO: 12 or a substantially similar sequence thereof; the CDRL1 region comprises the amino acid sequence of SEQ ID NO: 13 or a substantially similar sequence thereof; the CDRL2 region comprises the amino acid sequence of SEQ ID NO: 14 or a substantially similar sequence thereof; and the CDRL3 region comprises the amino acid sequence of SEQ ID NO: 15 or a substantially similar sequence thereof. 
     
     
         5 . The antibody or antigen-binding fragment thereof according to  claim 1 , which comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17 or a substantially similar sequence thereof, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19 or a substantially similar sequence thereof. 
     
     
         6 . The antibody or antigen-binding fragment thereof according to  claim 5 , wherein the heavy chain variable region is encoded by a nucleic acid sequence of SEQ ID NO: 16; and the light chain variable region is encoded by a nucleic acid sequence of SEQ ID NO: 18. 
     
     
         7 . The antibody or antigen-binding fragment thereof according to  claim 1 , which comprises a heavy chain variable region comprising the amino acid sequences of SEQ ID NO: 21 or a substantially similar sequence thereof; and a light chain variable region comprising the amino acid sequences of SEQ ID NO: 23 or a substantially similar sequence thereof. 
     
     
         8 . The antibody or antigen-binding fragment thereof according to  claim 7 , wherein the heavy chain variable region is encoded by a nucleic acid sequence of SEQ ID NO: 20; and the light chain variable region is encoded by a nucleic acid sequence of SEQ ID NO: 22. 
     
     
         9 . The antibody or antigen-binding fragment thereof according to  claim 1 , which comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 or a substantially similar sequence thereof; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 27 or a substantially similar sequence thereof. 
     
     
         10 . The antibody or antigen-binding fragment thereof according to  claim 9 , wherein the heavy chain variable region is encoded by a nucleic acid sequence of SEQ ID NO: 24 the light chain variable region is encoded by a nucleic acid sequence of SEQ ID NO: 26. 
     
     
         11 . The antibody or antigen-binding fragment thereof according to  claim 1 , which is conjugated with a therapeutic agent. 
     
     
         12 . The antibody or antigen-binding fragment thereof according to  claim 11 , wherein the therapeutic agent is selected from the group consisting of antimetabolites, alkylating agents, alkylating-like agents, DNA minor groove alkylating agents, anthracyclines, antibiotics, calicheamicins, antimitotic agents, topoisomerase inhibitors, HDAC inhibitor, proteasome inhibitors, and radioisotopes. 
     
     
         13 . The antibody or antigen-binding fragment thereof according to  claim 1 , which is expressed on a surface of a cell. 
     
     
         14 . The antibody or antigen-binding fragment thereof according to  claim 13 , wherein the cell is a T-cell. 
     
     
         15 . A method for inhibiting VEGFR-2-mediated signaling in a subject in need, comprising administering to the subject a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to  claim 1 . 
     
     
         16 . A method for treating diseases and/or disorders caused by or related to VEGFR-2 activity and/or signaling in a subject afflicted with the diseases and/or disorders, comprising administering to the subject a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to  claim 1 . 
     
     
         17 . A method for treating tumor in a subject afflicted with the tumor, comprising administering to the subject a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to  claim 1 . 
     
     
         18 . The method according to  claim 17 , wherein the tumor is a solid tumor. 
     
     
         19 . The method according to  claim 18 , wherein the tumor is selected from the group consisting of renal cell carcinoma, pancreatic carcinoma, breast cancer, head and neck cancer, prostate cancer, malignant gliomas, osteosarcoma, colorectal cancer, gastric cancer, malignant mesothelioma, multiple myeloma, ovarian cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, or melanoma. 
     
     
         20 . A method for inhibiting cell proliferation of endothelial cells in a subject in need, comprising administering to the subject a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to  claim 1 . 
     
     
         21 . A method for detecting human vascular endothelial growth factor receptor 2 in a sample comprising contacting the sample with the antibody or antigen-binding fragment thereof according to  claim 1 . 
     
     
         22 . The method according to  claim 21 , which is for detecting domains 6 to 7 of the VEGFR-2.