Targeted interferons demonstrate potent apoptotic and anti-tumor activities
Novel chimeric moieties that show significant efficacy against cancers are provided. In certain embodiments the chimeric moieties comprise a targeting moiety attached to an interferon. In certain embodiments, the chimeric moieties comprise fusion proteins where an antibody that specifically binds to a cancer marker is fused to interferon alpha (IFN-α) or interferon beta (IFN-β).
1. A method of inhibiting growth and/or proliferation of a rituximab-resistant cancer cell, said method comprising contacting said cancer cell with a chimeric construct comprising an interferon attached to an antibody that binds to a tumor-associated antigen, wherein said antibody is attached to said interferon by a linker where the amino acid sequence of said linker consists of the sequence SGGGGS (SEQ ID NO:81) or AEAAAKEAAAKAGS (SEQ ID NO:82), wherein said construct when contacted to said rituximab-resistant cancer cell results in the killing or inhibition of growth or proliferation of said cancer cell.
2. The method of claim 1 , wherein said cancer cell is a metastatic cell.
3. The method of claim 1 , wherein said cancer cell is in a solid tumor.
4. The method of claim 1 , wherein said cancer cell is a breast cancer cell.
5. The method of claim 1 , wherein said cancer cell is a B cell lymphoma.
6. The method of claim 1 , wherein said cancer cell is cell produced by a cancer selected from the group consisting of a B cell lymphoma, lung cancer, a bronchus cancer, a colorectal cancer, a prostate cancer, a breast cancer, a pancreas cancer, a stomach cancer, an ovarian cancer, a urinary bladder cancer, a brain or central nervous system cancer, a peripheral nervous system cancer, an esophageal cancer, a cervical cancer, a melanoma, a uterine or endometrial cancer, a cancer of the oral cavity or pharynx, a liver cancer, a kidney cancer, a biliary tract cancer, a small bowel or appendix cancer, a salivary gland cancer, a thyroid gland cancer, a adrenal gland cancer, an osteosarcoma, a chondrosarcoma, a liposarcoma, a testes cancer, and a malignant fibrous histiocytoma.
7. The method of claim 1 , wherein:
said contacting comprises systemically administering said chimeric moiety to a mammal; or
said contacting comprises administering said chimeric moiety directly into a tumor site; or
said contacting comprises intravenous administration of said chimeric moiety.
8. The method of claim 1 , wherein said cancer cell is a cancer cell in a human.
9. The method of claim 1 , wherein said cancer cell is a cancer cell in a non-human mammal.
10. The method of claim 1 , wherein said interferon is an interferon alpha.
11. The method of claim 1 , wherein said interferon is an interferon beta.
12. The method of claim 1 , wherein said construct is a recombinantly expressed fusion protein.
13. The method of claim 1 , wherein said antibody specifically binds a marker selected from the group consisting of CD20, HER3, HER2/neu, MUC-1, G250, mesothelin, gp100, tyrosinase, and MAGE.
14. The method of claim 1 , wherein said antibody is an antibody that binds CD20.
15. The method of claim 14 , wherein said antibody that comprises the complementarity determining regions (CDRs) of anti-CD20 (rituximab).
16. The method of claim 14 , wherein said antibody comprises the variable regions of anti-CD20 (rituximab).
17. The method of claim 1 , wherein said antibody is an antibody that binds HER2.