Methods of treatment by administering antibodies to notch receptors
The present invention relates to Notch-binding agents and Notch antagonists and methods of using the agents and/or antagonists for treating diseases such as cancer. The present invention provides antibodies that specifically bind to a non-ligand binding region of the extracellular domain of one or more human Notch receptor, such as Notch2 and/or Notch3, and inhibit tumor growth. The present invention further provides methods of treating cancer, the methods comprising administering a therapeutically effective amount of an antibody that specifically binds to a non-ligand binding region of the extracellular domain of a human Notch receptor protein and inhibits tumor growth.
1. A method of treating cancer in a subject, comprising administering a therapeutically effective amount of an isolated antibody that specifically binds human Notch2 and/or Notch3, wherein the antibody comprises:
(a) a heavy chain CDR1 comprising SSSGMS (SEQ ID NO:5), a heavy chain CDR2 comprising VIASSGSNTYYADSVKG (SEQ ID NO:6), and a heavy chain CDR3 comprising SIFYTT (SEQ ID NO:51) or GIFFAI (SEQ ID NO:7); and
(b) a light chain CDR1 comprising RASQSVRSNYLA (SEQ ID NO:8), a light chain CDR2 comprising GASSRAT (SEQ ID NO:9), and a light chain CDR3 comprising QQYSNFPI (SEQ ID NO:10).
2. The method of claim 1 , wherein the heavy chain CDR3 comprises SIFYTT (SEQ ID NO:51).
3. The method of claim 1 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, or an antibody fragment.
4. The method of claim 1 , wherein the antibody comprises:
(a) a heavy chain variable region having at least about 90% sequence identity to SEQ ID NO:50, SEQ ID NO:14, or SEQ ID NO:20; and
(b) a light chain variable region having at least about 90% sequence identity to SEQ ID NO:13 or SEQ ID NO:19.
5. The method of claim 1 , wherein the antibody comprises:
(a) a heavy chain variable region having at least about 95% sequence identity to SEQ ID NO:50, and
(b) a light chain variable region having at least about 95% sequence identity to SEQ ID NO:13.
6. The method of claim 1 , wherein the antibody comprises a heavy chain variable region of SEQ ID NO:50 and a light chain variable region of SEQ ID NO:13.
7. The method of claim 1 , wherein the cancer is a colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, lung cancer, or melanoma.
8. The method of claim 1 , further comprising administering a therapeutically effective amount of a second therapeutic agent to the subject.
9. The method of claim 8 , wherein the second therapeutic agent is a chemotherapeutic agent.
10. The method of claim 9 , wherein the chemotherapeutic agent is paclitaxel, gemcitabine, pemetrexed, carboplatin, or irinotecan.
11. The method of claim 8 , wherein the second therapeutic agent is an anti-angiogenic agent.
12. The method of claim 11 , wherein the anti-angiogenic agent is an antagonist of vascular endothelial cell growth factor (VEGF) or of a VEGF receptor.
13. The method of claim 8 , wherein the second therapeutic agent is a second antibody.
14. The method of claim 1 , wherein the subject is human.
15. A method of treating cancer in a subject, comprising administering a therapeutically effective amount of an isolated antibody that specifically binds human Notch2 and/or Notch3, wherein the antibody is encoded by the polynucleotide deposited with ATCC as PTA-9547 or the polynucleotide deposited with ATCC as PTA-10170.
16. A method of inhibiting Notch2 and/or Notch3 signaling in a cell, comprising contacting the cell with an effective amount of an isolated antibody that specifically binds human Notch2 and/or Notch3, wherein the antibody comprises:
(a) a heavy chain CDR1 comprising SSSGMS (SEQ ID NO:5), a heavy chain CDR2 comprising VIASSGSNTYYADSVKG (SEQ ID NO:6), and a heavy chain CDR3 comprising SIFYTT (SEQ ID NO:51) or GIFFAI (SEQ ID NO:7); and
(b) a light chain CDR1 comprising RASQSVRSNYLA (SEQ ID NO:8), a light chain CDR2 comprising GASSRAT (SEQ ID NO:9), and a light chain CDR3 comprising QQYSNFPI (SEQ ID NO:10).
17. A method of inhibiting angiogenesis in a subject, comprising administering an effective amount of an isolated antibody that specifically binds human Notch2 and/or Notch3, wherein the antibody comprises:
(a) a heavy chain CDR1 comprising SSSGMS (SEQ ID NO:5), a heavy chain CDR2 comprising VIASSGSNTYYADSVKG (SEQ ID NO:6), and a heavy chain CDR3 comprising SIFYTT (SEQ ID NO:51) or GIFFAI (SEQ ID NO:7); and
(b) a light chain CDR1 comprising RASQSVRSNYLA (SEQ ID NO:8), a light chain CDR2 comprising GASSRAT (SEQ ID NO:9), and a light chain CDR3 comprising QQYSNFPI (SEQ ID NO:10).
18. The method of claim 17 , which inhibits angiogenesis by modulating the function of pericytes and/or vascular smooth muscle cells.
19. The method of claim 17 , wherein the angiogenesis is tumor angiogenesis.
20. A method of inhibiting tumor growth in a subject, comprising administering an effective amount of an isolated antibody that specifically binds human Notch2 and/or Notch3, wherein the antibody comprises:
(a) a heavy chain CDR1 comprising SSSGMS (SEQ ID NO:5), a heavy chain CDR2 comprising VIASSGSNTYYADSVKG (SEQ ID NO:6), and a heavy chain CDR3 comprising SIFYTT (SEQ ID NO:51) or GIFFAI (SEQ ID NO:7); and
(b) a light chain CDR1 comprising RASQSVRSNYLA (SEQ ID NO:8), a light chain CDR2 comprising GASSRAT (SEQ ID NO:9), and a light chain CDR3 comprising QQYSNFPI (SEQ ID NO:10).
21. A method of reducing the tumorigenicity of a tumor in a subject, comprising administering an effective amount of an isolated antibody that specifically binds human Notch2 and/or Notch3, wherein the antibody comprises:
(a) a heavy chain CDR1 comprising SSSGMS (SEQ ID NO:5), a heavy chain CDR2 comprising VIASSGSNTYYADSVKG (SEQ ID NO:6), and a heavy chain CDR3 comprising SIFYTT (SEQ ID NO:51) or GIFFAI (SEQ ID NO:7); and
(b) a light chain CDR1 comprising RASQSVRSNYLA (SEQ ID NO:8), a light chain CDR2 comprising GASSRAT (SEQ ID NO:9), and a light chain CDR3 comprising QQYSNFPI (SEQ ID NO:10).
22. The method of claim 21 , wherein the frequency of cancer stem cells in the tumor is reduced.
23. The method of claim 21 , wherein the tumor is a colorectal tumor, breast tumor, pancreatic tumor, or melanoma.