Tumor targeted Tnf-related apoptosis inducing ligand fusion polypeptide, methods and uses therefor

Patent metadata

Field	Value
Publication number	US-9815882-B2
Application number	US-201514798045-A
Country	US
Kind code	B2
Filing date	Jul 13, 2015
Priority date	May 10, 2012
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

Fusion polypeptides comprising a TRAIL trimer and a targeting domain are disclosed. The targeting domain can be, in some embodiments, a sequence that binds MUC16, which is prevalent on some tumor cells such as pancreatic and ovarian tumor cells. A sequence that binds MUC 16 can be mesothelin or a MUC16-binding fragment thereof, such as amino acids 1-64 of mesothelin. A fusion polypeptide of the present teachings can induce apoptosis in a target cell such as a MUC16-expressing cancer cell. Also disclosed are nucleic acids encoding the fusion polypeptides, and methods of use of the fusion polypeptides and nucleic acids.

First claim

What is claimed is:

1. A fusion polypeptide comprising:
a mesothelin polypeptide selected from the group consisting of meso64 and mesothelinΔGPI; and
three consecutive extracellular domains of TNF-related apoptosis-inducing ligand (TRAIL) domains fused together in a head-to-tail configuration.

2. A fusion polypeptide in accordance with claim 1 , wherein the mesothelin polypeptide is meso64.

3. A fusion polypeptide in accordance with claim 1 , wherein the mesothelin polypeptide is mesothelinΔGPI.

4. A fusion polypeptide in accordance with claim 1 , further comprising a His-tag.

5. An anticancer therapeutic comprising the fusion polypeptide of claim 1 .

6. A nucleic acid comprising a sequence encoding the fusion polypeptide of claim 1 .

7. A vector comprising the nucleic acid of claim 6 .

8. A vector of claim 7 , wherein said vector is a plasmid.

9. A method of inducing apoptosis in a tumor cell, comprising contacting the tumor cell with the fusion polypeptide of claim 1 .

10. The method of claim 9 , wherein the tumor cell expresses MUC16.

11. The method of claim 9 , wherein the tumor cell is an ovarian cancer cell.

12. The method of claim 9 , wherein the tumor cell is a pancreatic cancer cell.

13. The method of claim 9 wherein the tumor cell is a breast cancer cell.

14. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the fusion polypeptide of claim 1 .

15. The method of claim 14 , wherein the cancer comprises MUC16-positive cells.

16. The method of claim 14 , wherein the cancer comprises ovarian cancer cells.

17. The method of claim 14 , wherein the cancer comprises pancreatic cancer cells.

18. The method of claim 14 , wherein the cancer comprises breast cancer cells.

Assignees

• Univ Washington

Inventors

• Spitzer Dirk
• Hawkins William G

Classifications

• C07K14/4747

  Apoptosis related proteins · CPC title

• C12N15/63

  Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression · CPC title

• C07K14/705 Primary

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• A61K38/177

  Receptors; Cell surface antigens; Cell surface determinants · CPC title

• A61K39/0001

  Archaeal antigens · CPC title