Method of treating cancer by administering a monoclonal antibody that binds human NOTCH2 and NOTCH3
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 to the subject a therapeutically effective amount of an isolated monoclonal antibody that specifically binds epidermal growth factor (EGF) repeat 10 of human NOTCH2 and EGF repeat 9 of human NOTCH3.
2. The method of claim 1 , wherein the antibody binds at least part of the sequence HKGAL (SEQ ID NO:28) within EGF repeat 10 of human NOTCH2.
3. The method of claim 2 , wherein the antibody binds at least part of the sequence HEDAI (SEQ ID NO:29) within EGF repeat 9 of human NOTCH3.
4. The method of claim 1 , wherein the antibody binds at least part of the sequence HEDAI (SEQ ID NO:29) within EGF repeat 9 of human NOTCH3.
5. The method of claim 1 , wherein the antibody is a recombinant antibody, a chimeric antibody, a humanized antibody, a human antibody, a bispecific antibody, a monospecific antibody, an antibody fragment, an IgG1 antibody, or an IgG2 antibody.
6. The method of claim 1 , wherein the cancer is a colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, lung cancer or melanoma.
7. The method of claim 1 , further comprising administering to the subject a therapeutically effective amount of at least one therapeutic agent.
8. The method of claim 7 , wherein the additional therapeutic agent is a chemotherapeutic agent or an anti-angiogenic agent.
9. The method of claim 8 , wherein the additional therapeutic agent is a chemotherapeutic agent selected from the group consisting of: a taxane, an anti-metabolite, a platinum complex, or a topoisomerase.
10. The method of claim 8 , wherein the additional therapeutic agent is an anti-angiogenic agent selected from the group consisting of: an antagonist of vascular endothelial cell growth factor (VEGF) or an antagonist of a VEGF receptor.
11. A method of inhibiting tumor growth in a subject, comprising administering to the subject an effective amount of a monoclonal antibody that specifically binds epidermal growth factor (EGF) repeat 10 of human NOTCH2 and EGF repeat 9 of human NOTCH3.
12. The method of claim 11 , wherein the antibody binds at least part of the sequence HKGAL (SEQ ID NO:28) within EGF repeat 10 of human NOTCH2.
13. The method of claim 12 , wherein the antibody binds at least part of the sequence HEDAI (SEQ ID NO:29) within EGF repeat 9 of human NOTCH3.
14. The method of claim 11 , wherein the antibody binds at least part of the sequence HEDAI (SEQ ID NO:29) within EGF repeat 9 of human NOTCH3.
15. A method of inhibiting Notch2 and/or Notch3 signaling in a cell, comprising contacting the cell with an effective amount of a monoclonal antibody that specifically binds epidermal growth factor (EGF) repeat 10 of human NOTCH2 and EGF repeat 9 of human NOTCH3.
16. The method of claim 15 , wherein the antibody binds at least part of the sequence HKGAL (SEQ ID NO:28) within EGF repeat 10 of human NOTCH2.
17. The method of claim 16 , wherein the antibody binds at least part of the sequence HEDAI (SEQ ID NO:29) within EGF repeat 9 of human NOTCH3.
18. The method of claim 15 , wherein the antibody binds at least part of the sequence HEDAI (SEQ ID NO:29) within EGF repeat 9 of human NOTCH3.