Tumor targeted TNF-related apoptosis inducing ligand fusion polypeptide and nucleic acids encoding the same
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 trimer of a TNF-related apoptosis-inducing ligand (TRAIL), comprising:
a mesothelin polypeptide; and
three consecutive extracellular TRAIL domains fused together in a head-to-tail configuration.
2. A trimer in accordance with claim 1 , further comprising a His-tag.
3. An anticancer therapeutic comprising a trimer in accordance with claim 1 .
4. A nucleic acid comprising a sequence encoding the trimer of claim 1 .
5. A vector comprising the nucleic acid of claim 4 .
6. A vector of claim 4 , wherein said vector is a plasmid.
7. A method of inducing apoptosis in a tumor cell, comprising contacting the tumor cell with a trimer of claim 1 .
8. The method of inducing apoptosis in a tumor cell in accordance with claim 7 , wherein the tumor cell expresses MUC16.
9. The method of inducing apoptosis in a tumor cell in accordance with claim 7 , wherein the tumor cell is an ovarian cancer cell.
10. The method of inducing apoptosis in a tumor cell in accordance with claim 7 , wherein the tumor cell is a pancreatic cancer cell.
11. The method of inducing apoptosis in a tumor cell in accordance with claim 7 , wherein the tumor cell is a breast cancer cell.
12. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a trimer of claim 1 .
13. The method of treating a cancer in a subject in accordance with claim 12 , wherein the cancer comprises MUC16-positive cells.
14. The method of treating a cancer in a subject in accordance with claim 12 , wherein the cancer comprises ovarian cancer cells.
15. The method of treating a cancer in a subject in accordance with claim 12 , wherein the cancer comprises pancreatic cancer cells.
16. The method of treating a cancer in a subject in accordance with claim 12 , wherein the cancer comprises breast cancer cells.