Claims for Patent: 8,785,385

Summary for Patent: 8,785,385

Title:	RTEF-1 variants and uses thereof
Abstract:	Disclosed are variant RTEF-1 polypeptides having an RTEF-1 amino acid sequence with one or more internal deletions, wherein the polypeptides reduce VEGF promoter activity. Some of the RTEF-1 polypeptides include an amino acid sequence that is at least 80% identical to the contiguous amino acids of 1) amino acids 24 to 47 of SEQ ID NO:15 and 2) each of SEQ ID NOs:16 and 17, but does not comprise the contiguous amino acids of SEQ ID NOs:8, 9, 11, or 12. Also disclosed are nucleic acids encoding the variant RTEF-1 polypeptides of the present invention. Pharmaceutical compositions that include the polypeptides and nucleic acids of the present invention are also disclosed. Methods of inducing cell contact inhibition, regulating organ size, and reducing intracellular YAP activity are also set forth, as well as methods of treating hyperproliferative diseases such as cancer using the pharmaceutical compositions of the present invention.
Inventor(s):	Stout; J. Timothy (Portland, OR), Appukuttan; Binoy (Portland, OR), McFarland; Trevor (Portland, OR), Dye; Anna (Portland, OR)
Assignee:	Research Development Foundation (Carson City, NV) Oregon Health & Science University (Portland, OR)
Application Number:	13/089,687
Patent Claims:	1. An isolated variant RTEF-1 polypeptide that reduces VEGF promoter activity comprising an amino acid sequence that is at least 95% identical to the contiguous amino acids of 1) amino acids 24 to 47 of SEQ ID NO:15 and 2) each of SEQ ID NOs:16 and 17, but does not comprise the contiguous amino acids of SEQ ID NOs:8, 9, 11, and 12, further wherein said polypeptide does not include an amino acid sequence consisting of amino acids 1-16 of SEQ ID NO:8. 2. The isolated variant RTEF-1 polypeptide of claim 1, comprising an amino acid sequence that is at least 97% identical to the contiguous amino acids of 1) amino acids 24 to 47 of SEQ ID NO:15 and 2) each of SEQ ID NOs:16 and 17. 3. The isolated variant RTEF-1 polypeptide of claim 1, comprising an amino acid sequence that is at least 99% identical to the contiguous amino acids of 1) amino acids 24 to 47 of SEQ ID NO:15 and 2) each of SEQ ID NOs:16 and 17. 4. The isolated variant RTEF-1 polypeptide of claim 1, wherein the polypeptide is at least 95% identical to SEQ ID NO:1. 5. The isolated RTEF-1 polypeptide of claim 4, wherein the polypeptide is at least 97% identical to SEQ ID NO:1. 6. The isolated RTEF-1 polypeptide of claim 5, wherein the polypeptide is at least 99% identical to SEQ ID NO:1. 7. The isolated RTEF-1 polypeptide of claim 6, wherein the polypeptide comprises SEQ ID NO:1. 8. The isolated RTEF-1 polypeptide of claim 1, wherein the polypeptide is at least 95% identical to SEQ ID NO:2. 9. The isolated RTEF-1 polypeptide of claim 8, wherein the polypeptide is at least 97% identical to SEQ ID NO:2. 10. The isolated RTEF-1 polypeptide of claim 8, wherein the polypeptide is at least 99% identical to SEQ ID NO:2. 11. The isolated RTEF-1 polypeptide of claim 10, wherein the RTEF-1 polypeptide comprises SEQ ID NO:2. 12. The isolated RTEF-1 polypeptide of claim 1, further comprising a cell internalization moiety or a nuclear localization sequence that is a polypeptide, an antibody, an aptamer or an avimer. 13. The isolated RTEF-1 polypeptide of claim 12, wherein the cell internalization moiety is a polypeptide comprising an HIV tat polypeptide, HSV-1 tegument protein VP22, or Drosophila antennopedia protein. 14. The isolated RTEF-1 polypeptide of claim 12, wherein the cell internalization moiety is a polypeptide comprising poly-arginine, poly-methionine or poly-glycine. 15. The isolated RTEF-1 polypeptide of claim 12, wherein the cell internalization moiety is a polypeptide comprising RMRRMRRMRR (SEQ ID NO:20). 16. The isolated RTEF-1 polypeptide of claim 12, wherein the cell internalization moiety is an antibody that is an IgA, an IgM, an IgE, an IgG, a Fab, a F(ab')2, a single chain antibody or a paratope peptide. 17. The isolated RTEF-1 polypeptide of claim 1, further comprising a cell secretion signal. 18. The isolated RTEF-1 polypeptide of claim 17, wherein the cell secretion signal comprises the human IL-2 secretion signal sequence (SEQ ID NO:23). 19. A kit comprising a predetermined quantity of a variant RTEF-1 polypeptide of claim 1 in one or more sealed vials. 20. A pharmaceutical composition comprising a) one or more variant RTEF-1 polypeptides as set forth in claim 1; and b) a pharmaceutically acceptable carrier. 21. The pharmaceutical composition of claim 20, comprising SEQ ID NO:1 or SEQ ID NO:2. 22. A method of inducing cell contact inhibition in a population comprising two or more cells, comprising contacting a cell of the population with an effective amount of a variant RTEF-1 polypeptide of claim 1, wherein cell contact inhibition in the population is induced. 23. A method of suppressing YAP activity in a cell, comprising contacting a cell with an effective amount of a variant RTEF-1 polypeptide of claim 1, wherein YAP activity in the cell is suppressed. 24. The method of claim 23, wherein the cell is contacted with a variant RTEF-1 polypeptide comprising a nuclear localization sequence and activity of YAP in the nucleus of the cell is suppressed. 25. The method of claim 23, wherein the variant RTEF-1 polypeptide does not include a nuclear localization sequence and wherein translocation of YAP into the nucleus of the cell is inhibited. 26. A method for treating a subject with a disorder associated with abnormal cell growth or abnormal cell proliferation, comprising administering to a subject with a disorder associated with abnormal cell growth or abnormal cell proliferation an effective amount of a pharmaceutical composition comprising a variant RTEF-1 polypeptide according to claim 1: wherein the disorder is treated. 27. The method of claim 26, wherein the disorder associated with abnormal cell growth or abnormal cell proliferation is an angiogenic disorder that is cancer, ocular neovascularization, an arterio-venous malformation, coronary restenosis, peripheral vessel restenosis, glomerulonephritis, or rheumatoid arthritis. 28. The method of claim 26, wherein the angiogenic disorder is cancer. 29. The method of claim 28, wherein the cancer is a cancer selected from the group consisting of cancer of breast cancer, lung cancer, prostate cancer, leukemia, lymphoma, head and neck cancer, brain cancer, stomach cancer, intestinal cancer, colorectal cancer, renal cancer, bladder cancer, testicular cancer, esophageal cancer, ocular melanoma, retinoblastoma, liver cancer, ovarian cancer, skin cancer, cancer of the tongue, cancer of the mouth, or metastatic cancer. 30. The method of claim 28, wherein the cancer is comprised of cancer cells that demonstrate detectable YAP in the nucleus and/or cytoplasm. 31. The method of claim 28, wherein the cancer cells demonstrate overexpression of YAP in the nucleus and/or cytoplasm compared to expression of YAP in the nucleus and/or cytoplasm of a cell of a similar tissue type that is not cancerous. 32. The method of claim 27, wherein the angiogenic disorder is ocular neovascularization. 33. The method of claim 32, wherein the ocular neovascularization is neovascularization due to age-related macular degeneration, neovascularization due to corneal graft rejection, neovascularization due to retinopathy of prematurity (ROP), or neovascularization due to diabetic retinopathy. 34. The method of claim 27, further comprising administering a secondary therapy for treatment of the antiangiogenic disorder. 35. The method of claim 34, wherein the secondary therapy is an antibody that binds to VEGF, a VEGF receptor, FGF, an FGF receptor, bevacizumab, ranibizumab, or pegaptanib sodium. 36. The method of 34, wherein the secondary therapy is an anticancer therapy that is chemotherapy, surgical therapy, immunotherapy or radiation therapy. 37. The method of claim 26, wherein the subject is a human. 38. The method of claim 26, wherein the composition is administered intravenously, intraarterially, epidurally, intrathecally, intraperitoneally, subcutaneously, orally, or topically. 39. The method of claim 32, wherein the composition is administered locally to the eye by topical drops, intracameral injection, subconjunctival injection, subtenon injection, or by intravitreous injection.

Details for Patent 8,785,385

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2030-04-19
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	06/30/2006		2030-04-19
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	08/10/2012		2030-04-19