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

Patent metadata

Field	Value
Publication number	US-10072061-B2
Application number	US-201715730441-A
Country	US
Kind code	B2
Filing date	Oct 11, 2017
Priority date	May 10, 2012
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

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 method of reducing metastatic potential of tumor cells in a subject in need thereof, comprising administering to a subject in need thereof a fusion polypeptide comprising a mesothelin polypeptide and three consecutive extracellular domains of TNF-related apoptosis-inducing ligand (TRAIL) fused together in a head-to-tail configuration.

2. A method in accordance with claim 1 , wherein the mesothelin polypeptide is a full-length mesothelin polypeptide.

3. A method in accordance with claim 1 , wherein the mesothelin polypeptide is meso64.

4. A method in accordance with claim 1 , wherein the mesothelin polypeptide is mesothelinΔGPI.

5. A method of reducing metastatic potential of a tumor cell in a subject in need thereof, comprising contacting a cell expressing MUC16 with a fusion polypeptide comprising a mesothelin polypeptide and three consecutive extracellular domains of TNF-related apoptosis-inducing ligand (TRAIL) fused together in a head-to-tail configuration.

6. A method in accordance with claim 5 , wherein the mesothelin polypeptide is a full-length mesothelin polypeptide.

7. A method in accordance with claim 5 , wherein the mesothelin polypeptide is meso64.

8. A method in accordance with claim 5 , wherein the mesothelin polypeptide is mesothelinΔGPI.

9. A method of selectively killing a MUC16-positive cell within a population of cells, comprising contacting the MUC16-positive cell with an effective amount of a fusion polypeptide comprising a mesothelin polypeptide and three consecutive extracellular domains of TNF-related apoptosis-inducing ligand (TRAIL) fused together in a head-to-tail configuration.

10. A method in accordance with claim 9 , wherein the mesothelin polypeptide is a full-length mesothelin polypeptide.

11. A method in accordance with claim 9 , wherein the mesothelin polypeptide is meso64.

12. A method in accordance with claim 9 , wherein the mesothelin polypeptide is mesothelinΔGPI.

Assignees

• Spitzer Dirk
• Hawkins William G
• Univ Washington

Inventors

• Spitzer Dirk
• Hawkins William G

Classifications

• C07K2319/74

  containing a fusion for binding to a cell surface receptor · CPC title

• A61K38/1761

  Apoptosis related proteins, e.g. Apoptotic protease-activating factor-1 (APAF-1), Bax, Bax-inhibitory protein(s)(BI; bax-I), Myeloid cell leukemia associated protein (MCL-1), Inhibitor of apoptosis [IAP] or Bcl-2 · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• C12N15/63

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

• C07K14/4747

  Apoptosis related proteins · CPC title