Claims for Patent: 9,062,121

Summary for Patent: 9,062,121

Title:	Stabilized STAT3 decoy oligonucleotides and uses therefore
Abstract:	The present invention is based, at least in part, on novel, unimolecular STAT3 oligonucleotide decoys exhibiting increased in vivo stability as compared to previously known decoys which are effective in inhibiting STAT3 when administered systemically. The invention is also based on pharmaceutical compositions comprising these unimolecular decoys, and methods for using these decoys in the treatment of cancer.
Inventor(s):	Grandis; Jennifer R. (Pittsburgh, PA), Johnson; Daniel (Glenshaw, PA), Ly; Danith (Pittsburgh, PA)
Assignee:	University of Pittsburgh--of the Commonwealth System of Higher Education (Pittsburgh, PA)
Application Number:	14/245,911
Patent Claims:	1. A cyclic double-stranded STAT3 oligonucleotide decoy, wherein (i) the decoy comprises a double-stranded oligonucleotide, or an analog thereof, having the sequence 5'-(N.sub.6-).sub.nCAN.sub.1TTCN.sub.2CN.sub.3TN.sub.4AN.sub.5TC-(N.sub.7- -).sub.m-3' (SEQ ID NO:1), wherein N.sub.3 is G; N.sub.1, N.sub.2, N.sub.4 and N.sub.5 are A, T, G or C; one, two, three or all of the following conditions are met: N.sub.1 is T; N.sub.1 is C; N.sub.4 is A and N.sub.5 is A; and N.sub.6 and N.sub.7 are A, T, G or C and n and m are independently 0-50; (ii) the two strands are joined at the ends by carbon spacers; (iii) the decoy binds to STAT3 protein under physiologic conditions and interferes with STAT3 binding to its target sequence; and (iv) the decoy has a serum half-life of greater than about 4 hours. 2. The STAT3 oligonucleotide decoy of claim 1, wherein the oligonucleotide comprises the sequence 5'-CATTTCCCGTAAATC-3' (SEQ ID NO:30). 3. The STAT3 oligonucleotide decoy of claim 1, wherein N.sub.2 is a pyrimidine. 4. The STAT3 oligonucleotide decoy of claim 1, wherein at least two of the following are met: N.sub.1 is T; N.sub.2 is C; N.sub.4 is A; and N.sub.5 is A. 5. The STAT3 oligonucleotide decoy of claim 1, wherein at least three of the following are met: N, is T; N.sub.2 is C; N.sub.4 is A; and N.sub.5 is A. 6. The STAT3 oligonucleotide decoy of claim 1, wherein the carbon spacer has 18 carbons. 7. The STAT3 oligonucleotide decoy of claim 1, wherein the carbon spacer is an ethylene glycol spacer. 8. The STAT3 oligonucleotide decoy of claim 7, wherein the carbon spacer comprises hexaethylene glycol. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a cyclic double-stranded STAT3 oligonucleotide decoy, wherein (i) the decoy comprises a double-stranded oligonucleotide, or an analog thereof, having the sequence 5'-(N.sub.6-).sub.nCA N.sub.1TTCN.sub.2C N.sub.3T N.sub.4A N.sub.5TC-(N.sub.7-).sub.m-3' (SEQ ID NO:1), wherein N.sub.3 is G; N.sub.1, N.sub.2, N.sub.4 and N.sub.5 are A, T, G or C; one, two, three or all of the following conditions are met: N.sub.1 is T; N.sub.2 is C; N.sub.4 is A and N.sub.5 is A; and N.sub.6 and N.sub.7 are A, T, G or C and n and m are independently 0-50; (ii) the two strands are joined at the ends by carbon spacers; (iii) the decoy binds to STAT3 protein under physiologic conditions and interferes with STAT3 binding to its target sequence; and (iv) the decoy has a serum half-life of greater than about 4 hours. 10. The pharmaceutical composition of claim 9, further comprising an anticancer agent. 11. The composition of claim 9, formulated as a parenteral dosage form. 12. The composition of claim 11, formulated as an intravenous dosage form. 13. The composition of claim 9, wherein the decoy is contained within a microbubble. 14. The composition of claim 9, wherein the decoy is associated with a peptide transduction domain. 15. The composition of claim 14, wherein the peptide transduction domain is TAT. 16. The composition of claim 9, wherein the STAT3 oligonucleotide decoy comprises the sequence 5'-CATTTCCCGTAAATC-3' (SEQ ID NO:30). 17. The composition of claim 9, wherein, in the STAT3 oligonucleotide decoy, N.sub.2 is a pyrimidine. 18. The composition of claim 9, wherein, in the STAT3 oligonucleotide decoy, at least two of the following are met: N.sub.1 is T; N.sub.2 is C; N.sub.4 is A; and N.sub.5 is A. 19. The composition of claim 9, wherein, in the STAT3 oligonucleotide decoy, at least three of the following are met: N.sub.1 is T; N.sub.2 is C; N.sub.4 is A; and N.sub.5 is A. 20. The composition of claim 9, wherein, in the STAT3 oligonucleotide decoy, the carbon spacer has 18 carbons. 21. The composition of claim 9, wherein, in the STAT3 oligonucleotide decoy, the carbon spacer is an ethylene glycol spacer. 22. The composition of claim 21, wherein the carbon spacer comprises hexaethylene glycol. 23. A method of inhibiting growth of a cancer in which STAT3 is activated in a patient, comprising administering to the patient an amount of a cyclic double-stranded STAT3 oligonucleotide decoy effective to inhibit growth of a cancer in a patient, thereby inhibiting growth of the cancer in the patient; wherein the oligonucleotide decoy (i) comprises a double-stranded oligonucleotide having the sequence 5'-(N.sub.6-).sub.nCAN.sub.1TTCN.sub.2CN.sub.3TN.sub.4AN.sub.5TC-(N.sub.7- -).sub.m-3' (SEQ ID NO: 1), wherein N.sub.3 is G; N.sub.1, N.sub.2, N.sub.4 and N.sub.5 are A, T, G or C; one, two, three or all of the following conditions are met: N.sub.1 is T; N.sub.2 is C; N.sub.4 is A and N.sub.5 is A; and N.sub.6 and N.sub.7 are A, T, or C and n and m are independently 0-50; (ii) the two strands are joined at the ends by two carbon spacers; (iii) the decoy binds to STAT3 protein under physiologic conditions and interferes with STAT3 binding to its target sequence; and (iv) the decoy has a serum half-life of greater than about 4 hours. 24. The method of claim 23, wherein the cancer is a squamous cell carcinoma. 25. The method of claim 24, wherein the cancer is a squamous cell carcinoma of the head and neck. 26. The method of claim 23, comprising administering to the patient a second anticancer therapy. 27. The method of claim 26, wherein the second anticancer therapy is one or both of a radiation therapy and treating the patient with an anticancer agent. 28. The method of claim 26, wherein the second anticancer therapy is a radiation therapy. 29. The method of claim 26, wherein the second anticancer therapy comprises treating the patient with an anticancer agent. 30. The methods of claim 26, wherein the anticancer therapy is an epidermal growth factor receptor (EGFR) antagonist. 31. The method of claim 30, wherein the epidermal growth factor receptor (EGFR) antagonist is cetuximab. 32. The method of claim 23, wherein the cancer is selected from the group consisting of multiple myeloma, HTLV-1 dependent leukemia, acute myelogenous leukemia, large granular lymphocyte leukemia, lymphoma, EBV-related Burkitt's lymphoma, mycosis fungoides, cutaneous T-cell lymphoma, non-Hodgkins lymphoma, anaplastic large-cell lymphoma, breast cancer, melanoma, ovarian cancer, lung cancer, pancreatic cancer, and prostate cancer. 33. The method of claim 23, wherein the STAT3 oligonucleotide decoy comprises the sequence 5'CATTTCCCGTAAATC-3' (SEQ ID NO:30). 34. The method of claim 23, wherein, in the STAT3 oligonucleotide decoy, N.sub.2 is a pyrimidine. 35. The method of claim 23, wherein, in the STAT3 oligonucleotide decoy, at least two of the following are met: N.sub.1 is T; N.sub.2 is C; N.sub.4 is A; and N.sub.5 is A. 36. The method of claim 23, wherein, in the STAT3 oligonucleotide decoy, at least three of the following are met: N.sub.1 is T; N.sub.2 is C; N.sub.4 is A; and N.sub.5 is A. 37. The method of claim 23, wherein, in the STAT3 oligonucleotide decoy, the carbon spacer has 18 carbons. 38. The method of claim 23, wherein, in the STAT3 oligonucleotide decoy, the carbon spacer is an ethylene glycol spacer. 39. The method of claim 38, wherein the carbon spacer comprises hexaethylene glycol.

Details for Patent 9,062,121

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2029-12-17
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2029-12-17