Claims for Patent: 8,765,705

Summary for Patent: 8,765,705

Title:	Oligonucleotides inhibiting cellular migration
Abstract:	Oligonucleotides inhibiting cellular migration, and the use of at least one inhibitor of protein expression, which inhibits the expression of TSP1 protein, or a protein, which controls the expression of TSP1 or mediates the activity of TSP1, or one inhibitor of protein activity, this inhibitor inhibiting the activity of the TSP1 protein, in particular the activity responsible for the stimulation of cell migration, or one protein which controls the expression or mediates the activity of TSP1 for the manufacture of a drug for the prevention or the treatment of primary tumors or invasive or metastatic tumors.
Inventor(s):	Cabon; Florence (Vitry, FR), Firlej; Virginie (Kremlin Bicetre, FR), Gallou-Kabani; Catherine (Gif-sur-Yvette, FR), Prevarskaya; Natalia (Rumegies, FR)
Assignee:	Centre National de la Recherche Scientifique (Paris, FR)
Application Number:	13/387,829
Patent Claims:	1. A method for the treatment of prostate tumors, and breast tumors, comprising administering to a subject in need thereof an effective amount of a compound that inhibits the expression of or the activity of Thrombospondin-1 (TSP1), wherein the compound comprises: a double-stranded oligonucleotide comprising two oligonucleotide sequences, (a) and (b), forming a hybrid, wherein the oligonucleotide sequence (a) is complementary to the oligonucleotide sequence (b), or presents less than 40% mismatches with said oligonucleotide sequence (b), and is complementary to a target nucleotide sequence coding for the TSP1 protein, or presents less than 40% mismatches with said target sequence; or a fragment of the above-defined double-stranded oligonucleotide, comprising two complementary fragments of the respective above-defined oligonucleotide sequences (a) and (b), provided that said fragment conserves the property of inhibiting the expression of TSP1; or a double-stranded oligonucleotide comprising two oligonucleotide sequences, (a) and (b), forming a hybrid, wherein each oligonucleotide sequence comprises at one of its 3' or 5' ends, one to five unpaired nucleotides, forming single-stranded ends extending beyond the hybrid, wherein the hybrid portion of the oligonucleotide sequence (a) is complementary to the oligonucleotide sequence (b), or presents less than 40% mismatches with said oligonucleotide sequence (b), and is complementary to a target nucleotide sequence coding for the TSP1 protein, or presents less than 40% mismatches with said target sequence; or a fragment of the above-defined double-stranded oligonucleotide, comprising two complementary fragments of the respective above-defined oligonucleotide sequences (a) and (b), provided that said fragment conserves the property of inhibiting the expression of TSP1 one. 2. The method according to claim 1, wherein the compound inhibits the expression of TSP1. 3. The method according to claim 1, wherein the compound is a combination product administered simultaneously, separately, or spread over time, said combination product comprising: at least one of said double-stranded oligonucleotides, and an anti-angiogenic agent, at least one of said double-stranded oligonucleotides, and an anti-tumoral agent, or at least one of said double-stranded oligonucleotides, and an anti-angiogenic agent, and an anti-tumoral agent. 4. The method according to claim 1, wherein the compound is administered in combination with an anti-tumoral therapy, radiotherapy or chemotherapy. 5. The method according to claim 1, wherein the compound comprises a double-stranded oligonucleotide selected from the group consisting of: (SEQ ID NO: 1 and SEQ ID NO: 2); (SEQ ID NO: 3 and SEQ ID NO: 4); (SEQ ID NO: 21 and SEQ ID NO: 22); (SEQ ID NO: 23 and SEQ ID NO: 24); (SEQ ID NO: 5 and SEQ ID NO: 6); (SEQ ID NO: 7 and SEQ ID NO: 8); (SEQ ID NO: 25 and SEQ ID NO: 26); and (SEQ ID NO: 27 and SEQ ID NO: 28). 6. The method according to claim 5, wherein the double-stranded oligonucleotide is selected from the group consisting of: (SEQ ID NO: 1 and SEQ ID NO: 2); (SEQ ID NO: 3 and SEQ ID NO: 4); (SEQ ID NO: 21 and SEQ ID NO: 22); and (SEQ ID NO: 23 and SEQ ID NO: 24). 7. The method according to claim 1, wherein the compound is siRNA. 8. The method according to claim 1, wherein the oligonucleotide sequence (a) comprises zero mismatches with the oligonucleotide sequence (b). 9. The method according to claim 1, wherein the oligonucleotide sequence (a) comprises one mismatch with the oligonucleotide sequence (b). 10. The method according to claim 1, wherein the oligonucleotide sequence (a) comprises less than 20% mismatches with the oligonucleotide sequence (b). 11. A method for inhibiting cell migration in tumor development wherein TSP-1 is expressed, comprising contacting a TSP-1 expressing tumor cell with a composition comprising a double-stranded oligonucleotide selected from the group consisting of: (SEQ ID NO: 1 and SEQ ID NO: 2); (SEQ ID NO: 3 and SEQ ID NO: 4); (SEQ ID NO: 21 and SEQ ID NO: 22); (SEQ ID NO: 23 and SEQ ID NO: 24); (SEQ ID NO: 5 and SEQ ID NO: 6); (SEQ ID NO: 7 and SEQ ID NO: 8); (SEQ ID NO: 25 and SEQ ID NO: 26); and (SEQ ID NO: 27 and SEQ ID NO: 28). 12. The method according to claim 11, wherein the double-stranded oligonucleotide is selected from the group consisting of: (SEQ ID NO: 1 and SEQ ID NO: 2); (SEQ ID NO: 3 and SEQ ID NO: 4); (SEQ ID NO: 21 and SEQ ID NO: 22); and (SEQ ID NO: 23 and SEQ ID NO: 24). 13. A pharmaceutical composition, comprising at least one double-stranded oligonucleotide selected from the group consisting of: (SEQ ID NO: 1 and SEQ ID NO: 2); (SEQ ID NO: 3 and SEQ ID NO: 4); (SEQ ID NO: 21 and SEQ ID NO: 22); and (SEQ ID NO: 23 and SEQ ID NO: 24), in association with a pharmaceutically acceptable vehicle. 14. The pharmaceutical composition according to claim 13, wherein the the at least one double stranded oligonucleotide is formulated for the administration to a subject at a dose in the range of 0.05 to 50 mg/kg. 15. The pharmaceutical composition according to claim 13, wherein the composition is a combination product for simultaneous, separate or spread over time use, said combination product comprising: the at least one double stranded oligonucleotide, and an anti-angiogenic agent, an anti-tumoral agent, or a combination thereof. 16. The pharmaceutical composition according to claim 15, wherein the anti-angiogenic agent is selected from the group consisting of Cilengitide, Vandetanib, Lenalidomide, Thalidomide, Arsenic Trioxide, Bevacizumab, anti-VEGFR-1, anti-VEGFR-2, anti-PDGFR, anti-FMS-FLT-3, and anti-TK1. 17. The pharmaceutical composition according to claim 15, wherein the anti-tumoral agent is selected from the group consisting of alkylating agents, Bendamustine, Temozolomide, Mechlorethamine, Cyclophosphamide, Carmustine, Cisplatine, Busulfan, Thiotepa, Decarbazine, anti-metabolite agents, Pentostatine, Methotrexate, Pemetrexed, Floxuridine, Fluorouracil, Cytaraine, Mercaptopurine, Thiguanine, cytotoxic antibiotics, Rubitecan, Mitomycine C, Daunorubicin, Doxorubicine, Bleomycin, Plicamycin, Mitoxantrone HCl, Oxaliplatine, plant derivatives, Vinorelbine, BMS 184476, Vincristine sulfate, Vinblastine, and Docetaxel taxol. 18. An isolated double-stranded oligonucleotide selected from the group consisting of: (SEQ ID NO: 1 and SEQ ID NO: 2); (SEQ ID NO: 3 and SEQ ID NO: 4); (SEQ ID NO: 21 and SEQ ID NO: 22); and (SEQ ID NO: 23 and SEQ ID NO: 24).

Details for Patent 8,765,705

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2029-07-31