FUSION PROTEINS THAT FACILITATE CANCER CELL DESTRUCTION

• US 20150353642A1
• Filed: 01/31/2014
• Published: 12/10/2015
• Est. Priority Date: 01/31/2013
• Status: Active Grant

• Current Assignee: Thomas Jefferson University (Main Line Health System)
• Original Assignee: Thomas Jefferson University (Main Line Health System)
• Inventors: Tykocinski, Mark L.
• Granted Patent: US 9,873,747 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/4703 Inhibitors; Suppressors
• CPC Class Codes: C07K 14/525 Tumour necrosis factor [TNF]
• CPC Class Codes: C07K 14/70575 NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 NGF C07K14/48, TNF C07K14/525
• CPC Class Codes: C07K 14/78 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/33 fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C07K 2319/74 containing a fusion for binding to a cell surface receptor

Abstract

Provided is a fusion protein comprising a polypeptide component that blocks binding of CD47 to SIRP alpha and a polypeptide that binds to and triggers a TRAIL receptor or Fas. Also provided is a method of treating cancer in a patient comprising administering the fusion protein of the invention to a patient in need of such treatment.

Claims

1. A fusion protein comprising Component A and Component B, wherein Component A comprises a CD47 blocker and Component B comprises a polypeptide that binds to and triggers a TRAIL receptor or Fas, and optionally comprising a linker between Components A and B.

2. The fusion protein of claim 1, wherein the N-terminus of Component A is fused to the C-terminus of Component B, either directly or indirectly via the linker.

3. The fusion protein of claim 1, wherein the CD47 blocker comprises at least a portion of the ectodomain of SIRP alpha.

4. The fusion protein of claim 1, wherein the CD47 blocker comprises at least a portion of the ectodomain of SIRP gamma.

5. The fusion protein of claim 1, wherein the CD47 blocker comprises at least a portion of the cell binding domain of thrombospondin-1.

6. The fusion protein of claim 1, wherein the CD47 blocker comprises a derivative of a monoclonal anti-CD47 antibody, the derivative selected from scFvCD47, V_HC_HCD47, and V_HHCD47.

7. The fusion protein of claim 1, wherein Component B comprises human TRAIL, or a fragment thereof.

8. The fusion protein of claim 3, wherein Component B comprises human TRAIL, or a fragment thereof.

9. The fusion protein of claim 4, wherein Component B comprises human TRAIL, or a fragment thereof.

10. The fusion protein of claim 5, wherein Component B comprises human TRAIL, or a fragment thereof.

11. The fusion protein of claim 6, wherein Component B comprises human TRAIL, or a fragment thereof.

12. The fusion protein of claim 1, wherein Component B comprises human Fas ligand, or a fragment thereof.

13. The fusion protein of claim 3, wherein Component B comprises human Fas ligand, or a fragment thereof.

14. The fusion protein of claim 4, wherein Component B comprises human Fas ligand, or a fragment thereof.

15. The fusion protein of claim 5, wherein Component B comprises human Fas ligand, or a fragment thereof.

16. The fusion protein of claim 6, wherein Component B comprises human Fas ligand, or a fragment thereof.

17. The fusion protein of claim 7, further comprising a trimerization domain.

18. The fusion protein of claim 1, comprising the amino acid sequence SEQ ID NO:

13.

19. The fusion protein of claim 1, comprising the amino acid sequence SEQ ID NO:

14.

20. The fusion protein of claim 1 consisting essentially of Component A and Component B, optionally comprising a linker between Component A and Component B.

21. The fusion protein of claim 2 consisting essentially of Component A and Component B, and a linker between Component A and Component B.

22. The fusion protein of claim 21, wherein the linker comprises one of SEQ ID NO:

17, SEQ ID NO;

19 and SEQ ID NO;

20.

23. The fusion protein of claim 22, wherein the linker comprises one of SEQ ID NO:

17, SEQ ID NO;

19 and SEQ ID NO;

20.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the fusion protein of claim 1.

25. A method of treating a proliferative disorder in a patient comprising administering a therapeutically effective amount of the fusion protein of claim 1 to a patient in need of such treatment.

26. The method of claim 25, wherein the proliferative disorder is cancer.

27. The method of claim 26, wherein the cancer is a solid tumor.

28. The method of claim 26, wherein the cancer is pancreatic cancer, breast cancer, ovarian cancer, bladder cancer, melanoma, glioblastoma, acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML).

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the fusion protein of claim 1, for treatment of a proliferative disorder.

30. The pharmaceutical composition of claim 29, wherein the proliferative disorder is cancer.

31. The pharmaceutical composition of claim 30, wherein the cancer is a solid tumor.

32. The pharmaceutical composition of claim 30, wherein the cancer is pancreatic cancer, breast cancer, ovarian cancer, bladder cancer, melanoma, glioblastoma, acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML).

33. The fusion protein of claim 12, further comprising a trimerization domain.