Anti c-Met antibodies
The present invention relates to antibodies that specifically bind to the human c-Met receptor protein and that act as strict antagonists of hepatocyte growth factor (HGF)-mediated activation of the c-Met receptor and also inhibit HGF-independent activation of the human c-Met protein.
1. An isolated polynucleotide comprising a nucleotide sequence encoding a heavy chain variable (VH) domain and a nucleotide sequence encoding a light chain variable (VL) domain of an antibody, or antigen binding fragment thereof, that binds to human c-Met protein, wherein said VH domain comprises the CDRH3, CDRH2, and CDRH1 of amino acid sequences SEQ ID NOs: 21, 83, and 19, respectively, and wherein said VL domain comprises the CDRL3, CDRL2, and CDRL1 of amino acid sequences SEQ ID NOs: 33, 32, and 31, respectively.
2. An expression vector comprising the polynucleotide of claim 1 operably linked to regulatory sequences which permit expression in a host cell or cell-free expression system.
3. A host cell or cell-free expression system containing the expression vector of claim 2 .
4. A method of producing a recombinant antibody or antigen binding fragment thereof, comprising
culturing the host cell or cell-free expression system of claim 3 under conditions which permit expression of the antibody or antigen binding fragment; and
recovering the expressed antibody or antigen binding fragment.
5. The isolated polynucleotide of claim 1 , wherein the nucleotide sequence encoding the VH domain further comprises a hinge region having fully human sequence.
6. The isolated polynucleotide of claim 1 , wherein the VH domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 92, 94, and 96.
7. The isolated polynucleotide of claim 1 , wherein the VL domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 93, 95, and 97.
8. The isolated polynucleotide of claim 1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 92, and the VL domain comprises the amino acid sequence of SEQ ID NO: 93.
9. The isolated polynucleotide of claim 1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 94, and the VL domain comprises the amino acid sequence of SEQ ID NO: 95.
10. The isolated polynucleotide of claim 1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 96, and the VL domain comprises the amino acid sequence of SEQ ID NO: 97.
11. An isolated polynucleotide comprising a nucleotide sequence encoding a heavy chain variable (VH) domain of an antibody, or antigen binding fragment thereof, that binds to human c-Met protein, wherein said VH domain comprises the CDRH3, CDRH2, and CDRH1 of amino acid sequences SEQ ID NOs: 21, 83, and 19, respectively.
12. The isolated polynucleotide of claim 11 , wherein the VH domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 92, 94, and 96.
13. The isolated polynucleotide of claim 12 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 92.
14. The isolated polynucleotide of claim 12 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 94.
15. The isolated polynucleotide of claim 12 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 96.
16. The isolated polynucleotide of claim 12 , selected from the group consisting of SEQ ID NOs: 100, 102, and 104.
17. The isolated polynucleotide of claim 11 , wherein the nucleotide sequence encoding the VH domain further comprises a hinge region having fully human sequence.
18. An isolated polynucleotide comprising a nucleotide sequence encoding a light chain variable (VL) domain of an antibody, or antigen binding fragment thereof, that binds to human c-Met protein, wherein said VL domain comprises the CDRL3, CDRL2, and CDRL1 of amino acid sequences SEQ ID NOs: 33, 32, and 31, respectively.
19. The isolated polynucleotide of claim 18 , wherein the VL domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 93, 95, and 97.
20. The isolated polynucleotide of claim 19 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 93.
21. The isolated polynucleotide of claim 19 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 95.
22. The isolated polynucleotide of claim 19 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 97.
23. The isolated polynucleotide of claim 19 , selected from the group consisting of SEQ ID NOs: 101, 103, and 105.
24. The isolated polynucleotide of claim 18 , wherein the nucleotide sequence encoding the VH domain further comprises a hinge region having fully human sequence.