Use of the combination of semaphorin-4D inhibitory molecules and VEGF inhibitory molecules to inhibit angiogenesis

1. A method for inhibiting angiogenesis in a human subject, comprising administering to the subject an effective amount of a first isolated binding molecule comprising a heavy chain variable region (VH) polypeptide comprising VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and a light chain variable region (VL) polypeptide comprising VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences comprising SEQ ID NOs: 14, 15 and 16, respectively, wherein the first isolated binding molecule specifically binds to semaphorin-4D (SEMA4D) and an effective amount of a second isolated binding molecule which specifically binds to VEGF and inhibits the interaction of VEGF with a VEGF receptor.

2. The method of claim 1 , wherein the first binding molecule hibits SEMA4D interaction with plexin-B1.

3. The method of claim 1 , wherein the first binding molecule hibits SEMA4D-mediated plexin B1 signal transduction.

4. The method of claim 1 , wherein the first isolated binding molecule specifically binds to the same SEMA4D epitope as a reference monoclonal antibody selected from the group consisting of VX15/2503, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 9 and the VL comprises the amino acid sequence of SEQ ID NO: 17, or monoclonal antibody 67, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 10 and the VL comprises the amino acid sequence of SEQ ID NO: 18.

5. The method of claim 1 , wherein the first isolated binding molecule comprises an antibody or antigen-binding fragment thereof.

6. The method of claim 5 , wherein the antibody or antigen-binding fragment thereof is monoclonal antibody VX15/2503, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 9 and the VL comprises the amino acid sequence of SEQ ID NO: 17, or monoclonal antibody 67, composing a heavy chain variable domain (VH) and a light chain variable domain (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 10 and the VL comprises the amino acid sequence of SEQ ID NO: 18.

7. The method of claim 1 wherein the first isolated binding molecule competitively inhibits a reference monoclonal antibody selected from the group consisting of VX15/2503, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 9 and the VL comprises the amino acid sequence of SEQ ID NO: 17, and monoclonal antibody 67, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 10 and the VL comprises the amino acid sequence of SEQ ID NO: 18, from specifically binding to SEMA4D.

8. The method of claim 1 , wherein the VEGF receptor is VEGFR1 or VEGFR2.

9. The method of claim 1 , wherein the second binding molecule inhibits phosphorylation of VEGFR2 by VEGF.

10. The method of claim 1 , wherein the inhibition of angiogenesis occurs independently of metastases inhibition.

11. The method of claim 1 , wherein the subject has cancer.

12. The method of claim 11 , wherein the cancer is selected from the group consisting of sarcoma, breast, ovarian, head and neck, pancreatic, prostate, lung, kidney, colorectal, brain, gastric, bladder, esophageal and a combination thereof.

13. A method of alleviating cancer in a human subject, comprising administering to the subject an effective amount of a first isolated binding molecule comprising a heavy chain variable region (VH) polypeptide comprising VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and a light chain variable region (VL) polypeptide comprising VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences comprising SEQ ID NOs: 14, 15, and 16, respectively, wherein the first isolated binding molecule specifically binds to semaphorin-4D (SEMA4D) and an effective amount of a second isolated binding molecule which specifically binds to VEGF and inhibits the interaction of VEGF with a VEGF receptor wherein the first isolated binding molecule and second isolated binding molecule act to inhibit angiogenesis.

14. A method for inhibiting angiogenesis in a human subject, comprising administering to the subject an effective amount of a first isolated binding molecule comprising a heavy chain variable region (VH) polypeptide comprising VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and a light chain variable region (VL) polypeptide comprising VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences comprising SEQ ID NOs: 14, 15, and 16, respectively, wherein the first isolated binding molecule inhibits interaction of semaphorin-4D (SEMA4D) with Plexin-B1 and an effective amount of a second isolated binding molecule whirl inhibits interaction of VEGF with VEGFR2.

15. The method of claim 14 , wherein the second isolated binding molecule is selected from the group consisting of an anti-VEGF and an anti-VEGFR2 binding molecule.

16. The method of claim 14 , wherein the subject has cancer.

17. The method of any one of claims 1 to 7 , 8 - 12 , 13 - 14 , 15 or 16 , wherein the first binding molecule and the second binding molecule are administered separately or concurrently.

18. The method of claim 1 wherein the of the VH of the first isolated binding molecule comprises an amino acid sequence at least 90% identical to SEQ ID NO: 9 or SEQ ID NO: 10.

19. The method of claim 1 , wherein the VL of the first isolated binding molecule comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 or SEQ ID NO: 18.

20. The method of claim 11 , wherein the inhibition of angiogenesis results in a decrease in vascular density in the cancer.

21. The method of claim 18 , wherein the VH of the first isolated binding molecule comprises the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10.

22. The method of claim 19 , wherein the VL of the first isolated binding molecule comprises the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 18.