Claims for Patent: 9,278,124

Summary for Patent: 9,278,124

Title:	Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods
Abstract:	Provided herein are diagnostic methods for identifying subjects susceptible to treatment with a hypoxia-activated agent, and related methods. Also provided herein are methods of monitoring treatments with anti-hyaluronan agents, and related methods.
Inventor(s):	Shepard; H. Michael (San Diego, CA), Li; Xiaoming (San Diego, CA), Thompson; Curtis (Encinitas, CA)
Assignee:	Halozyme, Inc. (San Diego, CA)
Application Number:	13/998,269
Patent Claims:	1. A method of treating a subject having a hypoxia-related disease or condition, comprising: a) measuring the level or amount of hyaluronan (HA) in a sample from a subject, whereby if the HA is at or above a predetermined level, the subject is susceptible to treatment with a hypoxia-activated agent, wherein: the HA is measured by detecting binding of a HA-binding protein (HABP) to the sample, and the HABP comprises a Tumor necrosis factor-Stimulated Gene-6 (TSG-6) link module (LM) or a sufficient portion thereof that specifically binds to HA; b) selecting a susceptible subject for treatment with a hyaluronidase and a hypoxia-activated agent; and c) administering a soluble hyaluronidase and a therapeutically effective amount of a hypoxia-activated agent to the subject, wherein the soluble hyaluronidase and the hypoxia-activated agent are administered simultaneously, sequentially or intermittently in any order, to thereby treat the subject. 2. The method of claim 1, wherein the hypoxia-related disease or condition is a hyperproliferative disease or condition. 3. The method of claim 1, wherein the hypoxia-related disease or condition is cancer, angiogenesis or an angiogenesis related disorder. 4. The method of claim 1, wherein the sample is selected from among a tissue, cell and bodily fluid. 5. The method of claim 1, wherein the sample is from a tumor. 6. The method of claim 1, wherein the predetermined level is the level or amount of the HA in a control or reference sample. 7. The method of claim 6, wherein the control or reference sample is selected from among: a) an analogous sample from a subject who does not have a hypoxia-related disease or condition; b) an analogous sample from a subject known to express low hyaluronan in the sample; and c) a cell line. 8. The method of claim 1, wherein: the predetermined level is the mean or median level or amount of HA in a sample from a subject who does not have a hypoxia-related disease or condition; or the predetermined level is the mean or median level or amount of HA in a sample from a subject known to have a hypoxia-related disease or condition. 9. The method of claim 1, wherein the subject is selected and treated if the level or amount is elevated at least 0.5-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to the predetermined level. 10. The method of claim 1, wherein the sample is a bodily fluid that is plasma and the predetermined level of HA is at least or above 0.010 .mu.g HA/mL. 11. The method of claim 1, wherein the sample is a tumor and a subject is selected for treatment if moderate to high hyaluronan is measured. 12. The method of claim 11, wherein moderate to high hyaluronan is measured if hyaluronan is present on at least 10%, 10% to 25%, or greater than 25% of the tumoral area. 13. The method of claim 1, wherein the TSG-6-LM has the sequence of amino acids set forth in SEQ ID NOS: 207, 360, 417 or 418, or a sequence of amino acids comprising at least 85% amino acid sequence identity to the sequence of amino acids set forth in SEQ ID NOS: 207, 360, 417 or 418 and specifically binds HA. 14. The method of claim 1, wherein the TSG-6 link module is modified to reduce or eliminate binding to heparin. 15. The method of claim 14, wherein the TSG-6 link module comprises an amino acid replacement at an amino acid position corresponding to amino acid residue 20, 34, 41, 54, 56, 72 or 84 set forth in SEQ ID NO:360, whereby a corresponding amino acid residue is identified by alignment to a TSG-6-LM set forth in SEQ ID NO:360. 16. The method of claim 15, wherein TSG-6 link module comprises an amino acid replacement corresponding to amino acid replacement K20A, K34A and/or K41A in a TSG-6-LM set forth in SEQ ID NO:360 or the replacement at the corresponding residue in another TSG-6-LM. 17. The method of claim 16, wherein the HABP comprises a link module set forth in SEQ ID NO:361 or 416 or a sequence of amino acids comprising at least 85% amino acid sequence identity to the sequence of amino acids set forth in SEQ ID NO:361 or 416 that specifically binds HA. 18. The method of claim 1, wherein the HABP is a multimer comprising a first HA-binding domain linked directly or indirectly via a linker to a multimerization domain and a second HA-binding domain linked directly or indirectly via a linker to a multimerization domain and wherein the first and second HA-binding domain each is a TSG-6 link module (LM), a variant thereof or a sufficient portion thereof that specifically binds to HA. 19. The method of claim 18, wherein the TSG-6-LM comprises the sequence of amino acids set forth in SEQ ID NOS: 207, 360, 361, 416, 417 or 418 or a sequence of amino acids comprising at least 85% amino acid sequence identity to the sequence of amino acids set forth in SEQ ID NOS: 207, 360, 361, 416, 417 or 418 that specifically binds HA. 20. The method of claim 18, wherein the multimerization domain is selected from among an immunoglobulin constant region (Fe), a leucine zipper, complementary hydrophobic regions, complementary hydrophilic regions, compatible protein-protein interaction domains, free thiols that forms an intermolecular disulfide bond between two molecules, and a protuberance-into-cavity and a compensatory cavity of identical or similar size that form stable multimers. 21. The method of claim 18, wherein the multimerization domain is an Fc domain or a variant thereof that effects multimerization. 22. The method of claim 21, wherein the HABP is a fusion protein that contains a TSG-6 link module and an immunoglobulin Fc domain. 23. The method of claim 22, wherein the HABP is TSG-6-LM-Fc and comprises the sequence of amino acids set forth as amino acids 21-349 of SEQ ID NO:212 or 215 or a sequence of amino acids that exhibits at least 85% sequence identity to amino acids 21-349 of SEQ ID NO: 212 or 215 and specifically binds HA. 24. The method of claim 22, wherein the HABP is TSG-6-LM-Fc and the polypeptide is encoded by a nucleic acid molecule that encodes the sequence of amino acids set forth in SEQ ID NO:212 or 215 or a sequence of amino acids that exhibits at least 85% amino acid sequence identity to SEQ ID NO:212 or 215 and specifically binds HA. 25. The method of claim 1, wherein the hypoxia-activated agent is a hypoxia-activated prodrug. 26. The method of claim 25, wherein the hypoxia-activated prodrug comprises a bioreductive group selected from among a quinone, aromatic N-oxide, aliphatic N-oxide, nitroheterocyclic compound and transition-metal complex. 27. The method of claim 25, wherein the hypoxia-activated prodrug comprises an anti-neoplastic agent. 28. The method of claim 27, wherein the anti-neoplastic agent is a pan-Her inhibitor. 29. The method of claim 25, wherein the hypoxia-activated prodrug is selected from among a mitomycin C, porfiromycin, cyclopropamitosene, diaziquone, streptonigrin, EO9, RH1, tirapazamine, CEN-209, AQ4N, Nitracrine N-Oxide, PR-104, SN28343, SN29303, SN29730, KS119W, NLCQ-1, RSU1069, RB6145, CB1954, SN23862, SN24771, TH-281, TH-308, TH-302, TH1332, TH1431, SN29966, SN32807, PR-509 or PR-610 and derivatives or analogs thereof. 30. The method of claim 25, wherein the hypoxia-activated prodrug is a conjugate comprising a hypoxia-activated prodrug linked directly or indirectly to a biomacromolecule that targets to a tumor. 31. The method of claim 30, wherein the biomacromolecule is selected from among apo-transferrin, Fe-transferrin, Ru-transferrin, Ti-transferrin, Ga-transferrin, Pt-transferrin, somatostatin, epidermal growth factor, folic acid and transcobalamin. 32. The method of claim 2, wherein the hyperproliferative disease is a cancer. 33. The method of claim 32, wherein the cancer is a tumor or a solid tumor. 34. The method of claim 32, wherein the disease or condition is cancer selected from among any one or more of breast cancer, pancreatic cancer, ovarian cancer, colon cancer, lung cancer, non-small cell lung cancer, in situ carcinoma (ISC), squamous cell carcinoma (SCC), thyroid cancer, cervical cancer, uterine cancer, prostate cancer, testicular cancer, brain cancer, bladder cancer, stomach cancer, hepatoma, melanoma, glioma, retinoblastoma, mesothelioma, myeloma, lymphoma, and leukemia. 35. The method of claim 1, comprising administering a corticosteroid prior to administration of the soluble hyaluronidase or after administration of the soluble hyaluronidase, wherein the corticosteroid is administered in an amount sufficient to ameliorate an adverse effect in the subject from the administered hyaluronan degrading enzyme. 36. The method of claim 1, wherein the subject is a human. 37. The method of claim 1, wherein the soluble hyaluronidase is a human hyaluronidase. 38. The method of claim 1, wherein the soluble hyaluronidase is a PH20 hyaluronidase. 39. The method of claim 38, wherein the hyaluronidase is bovine PH20, ovine PH20 or a soluble human PH20 that lacks all or a portion of the GPI anchor. 40. The method of claim 39, wherein the PH20 hyaluronidase comprises the sequence of amino acids set forth in any of SEQ ID NOS: 4-9, 47, 48, 150-171 and 183-189 or a sequence of amino acids that exhibits at least 85% sequence identity to any of SEQ ID NOS: 4-9, 47, 48, 150-170 and 183-189 and exhibits hyaluronidase activity. 41. The method of claim 1, wherein the soluble hyaluronidase is modified by conjugation to a polymer. 42. The method of claim 41, wherein the polymer is PEG and the soluble hyaluronidase is PEGylated. 43. The method of claim 42, wherein the soluble hyaluronidase is PEGPH20. 44. The method of claim 40, wherein the hyaluronidase is modified by conjugation to a polymer. 45. The method of claim 44, wherein the polymer is PEG and the soluble hyaluronidase is PEGylated. 46. The method of claim 40, wherein the PH20 hyaluronidase consists of a sequence of amino acids having at least 98% sequence identity to the polypeptides that consist of the sequence of amino acid residues set forth in SEQ ID NO:48. 47. The method of claim 46, wherein the hyaluronidase is modified by conjugation to a polymer. 48. The method of claim 47, wherein the polymer is PEG and the soluble hyaluronidase is PEGylated. 49. The method of claim 48, wherein the HABP comprises a TSG-6-LM multimer. 50. The method of claim 1, further comprising administering a glucocorticoid prior to or after the hyaluronidase. 51. The method of claim 45, further comprising administering a glucocorticoid prior to or after the hyaluronidase.

Details for Patent 9,278,124

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	May 05, 2004		2032-10-16
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	December 02, 2004		2032-10-16
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	October 26, 2004		2032-10-16
Akorn, Inc.	HYDASE	hyaluronidase	Injection	021716	October 25, 2005		2032-10-16