Compositions and methods for diagnosing and treating cancer
An isolated antibody that specifically binds to an extracellular domain of human DLL4 and affects growth of a tumor comprising cancer stem cells is described. Also described is a method of treating cancer comprising administering a therapeutically effective amount of an anti-DLL4 antibody.
1. A method of inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of a monoclonal antibody that specifically binds human delta-like ligand 4 (DLL4), wherein the antibody is selected from the group consisting of:
a) an antibody comprising:
i. a heavy chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:1); CDR2 (SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4); and CDR3 (SEQ ID NO:5), and
ii. a light chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:9); CDR2 (SEQ ID NO:10); and CDR3 (SEQ ID NO:11); and
b) an antibody comprising:
i. a heavy chain variable region comprising amino acids selected from the group consisting of: SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, or
ii. a light chain variable region comprising SEQ ID NO:12.
2. The method of claim 1 , wherein the antibody comprises:
a) a heavy chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:1), CDR2 (SEQ ID NO:3), and CDR3 (SEQ ID NO:5), and
b) a light chain variable region comprises CDR amino acid sequences CDR1 (SEQ ID NO: 9); CDR2 (SEQ ID NO:10); and CDR3 (SEQ ID NO:11).
3. The method of claim 1 , wherein the antibody comprises a heavy chain variable region comprising SEQ ID NO:7 and a light chain variable region comprising SEQ ID NO:12.
4. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a monoclonal antibody that specifically binds DLL4, wherein the antibody is selected from the group consisting of:
a) an antibody comprising:
i. a heavy chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:1); CDR2 (SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4); and CDR3 (SEQ ID NO:5), and
ii. a light chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:9); CDR2 (SEQ ID NO:10); and CDR3 (SEQ ID NO:11); and
b) an antibody comprising:
i. a heavy chain variable region comprising amino acids selected from the group consisting of: SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, or
ii. a light chain variable region comprising SEQ ID NO:12.
5. The method of claim 4 , wherein the antibody comprises:
a) a heavy chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:1), CDR2 (SEQ ID NO:3), and CDR3 (SEQ ID NO:5), and
b) a light chain variable region comprises CDR amino acid sequences CDR1 (SEQ ID NO: 9); CDR2 (SEQ ID NO:10); and CDR3 (SEQ ID NO:11).
6. The method of claim 5 , wherein the antibody comprises a heavy chain variable region comprising SEQ ID NO:7.
7. The method of claim 5 , wherein the antibody comprises a light chain variable region comprising SEQ ID NO:12.
8. The method of claim 5 , wherein the antibody comprises a heavy chain variable region comprising SEQ ID NO:7, and a light chain variable region comprising SEQ ID NO:12.
9. The method of claim 8 , wherein the antibody is a chimeric, bispecific, or humanized antibody.
10. The method of claim 8 , wherein the antibody is a humanized antibody.
11. The method of claim 8 , wherein the cancer is colorectal cancer, breast cancer, lung cancer, ovarian cancer, liver cancer, prostate cancer, kidney cancer, or pancreatic cancer.
12. The method of claim 11 , wherein the cancer is lung cancer.
13. The method of claim 12 , wherein the lung cancer is non-small cell lung cancer.
14. The method of claim 11 , wherein the cancer is pancreatic cancer.
15. The method of claim 14 , where the pancreatic cancer is metastatic.
16. The method of claim 11 , wherein the cancer is ovarian cancer.
17. The method of claim 11 , wherein the cancer is breast cancer.
18. The method of claim 4 , wherein the antibody is an antigen-binding fragment.
19. The method of claim 4 , wherein the antibody is a chimeric, bispecific, or humanized antibody.
20. The method of claim 19 , wherein the antibody is a humanized antibody.
21. The method of claim 4 , wherein the antibody is an IgG antibody.
22. The method of claim 21 , wherein the antibody is an IgG 2 antibody.
23. The method of claim 21 , wherein the antibody is an IgG 1 antibody.
24. The method of claim 20 , wherein the antibody is an IgG 2 antibody.
25. The method of claim 20 , wherein the antibody is an IgG 1 antibody.
26. The method of claim 4 , wherein the cancer is colorectal cancer, breast cancer, lung cancer, ovarian cancer, liver cancer, prostate cancer, kidney cancer, or pancreatic cancer.
27. The method of claim 2 , wherein the antibody is a chimeric, bispecific, or humanized antibody.
28. The method of claim 27 , wherein the antibody is a humanized antibody.
29. The method of claim 4 , further comprising administering a second therapeutic agent to the subject.
30. The method of claim 29 , wherein the second therapeutic agent is a chemotherapeutic agent.
31. The method of claim 29 , wherein the second therapeutic agent is a second therapeutic antibody.
32. The method of claim 29 , wherein the second therapeutic agent is radiation therapy.