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