Claims for Patent: 8,563,689

Summary for Patent: 8,563,689

Title:	Methods for regulating inflammatory mediators and peptides for useful therein
Abstract:	The present invention includes methods of modulating cellular secretory processes. More specifically the present invention relates to modulating or reducing the release of inflammatory mediators from inflammatory cells by inhibiting the mechanism associated with the release of inflammatory mediators from the vesicles or granules in the inflammatory cells in a subject with a chronic inflammatory disease. In this regard, the present invention discloses an intracellular signaling mechanism that illustrates several novel intracellular targets for pharmacological intervention in disorders involving secretion of inflammatory mediators from vesicles in inflammatory cells. MANS peptide and active fragments thereof are useful in such methods.
Inventor(s):	Takashi; Shuji (Nagano, JP), Parikh; Indu (Chapel Hill, NC), Adler; Kenneth B. (Raleigh, NC), Martin; Linda D. (Apex, NC), Li; Yuehua (Pearland, TX)
Assignee:	North Carolina State University (Raleigh, NC) Biomarck Pharmaceuticals, Ltd. (Raleigh, NC)
Application Number:	12/478,491
Patent Claims:	1. A method of inhibiting release of an inflammatory mediator associated with a chronic inflammatory disease in a subject comprising contacting an inflammatory cell in the subject suffering from a chronic inflammatory disease, which cell comprises the inflammatory mediator contained within a granule inside the cell, with at least one active myristoylated N-terminal fragment of a MANS peptide (SEQ ID NO:1), wherein said fragment comprises at least six contiguous amino acids of said MANS peptide, in an effective amount to reduce the MARCKS-related release of the inflammatory mediator from the inflammatory cell. 2. The method of claim 1, wherein said inflammatory mediator is selected from the group consisting of myeloperoxidase (MPO), eosinophil peroxidase (EPO), major basic protein (MBP), lysozyme, granzyme, histamine, proteoglycan, protease, a chemotactic factor, cytokine, a metabolite of arachidonic acid, defensin, bactericidal permeability-increasing protein (BPI), elastase, cathepsin G, cathepsin B, cathepsin D, beta-D-glucuronidase, alpha-mannosidase, phospholipase A.sub.2, chondroitin-4-sulphate, proteinase 3, lactoferrin, collagenase, complement activator, complement receptor, N-formylmethionyl-leucyl-phenylalanine (FMLP) receptor, laminin receptor, cytochrome b.sub.558, monocyte-chemotactic factor, histaminase, vitamin B12 binding protein, gelatinase, plasminogen activator, and a combination thereof. 3. The method according to claim 1, wherein said active fragment can be selected from the group consisting of N-myristoyl-GAQFSKTAAKGEAAAERPGEAAV (SEQ ID NO: 20); N-myristoyl-GAQFSKTAAKGEAAAERPGEAA (SEQ ID NO: 3); N-myristoyl-GAQFSKTAAKGEAAAERPGEA (SEQ ID NO: 4); N-myristoyl-GAQFSKTAAKGEAAAERPGE (SEQ ID NO: 5); N-myristoyl-GAQFSKTAAKGEAAAERPG (SEQ ID NO: 6); N-myristoyl-GAQFSKTAAKGEAAAERP (SEQ ID NO: 7); N-myristoyl-GAQFSKTAAKGEAAAER (SEQ ID NO: 8); N-myristoyl-GAQFSKTAAKGEAAAE (SEQ ID NO: 9); N-myristoyl-GAQFSKTAAKGEAAA (SEQ ID NO: 10); N-myristoyl-GAQFSKTAAKGEAA (SEQ ID NO: 11); N-myristoyl-GAQFSKTAAKGEA (SEQ ID NO: 12); N-myristoyl-GAQFSKTAAKGE (SEQ ID NO: 13); N-myristoyl-GAQFSKTAAKG (SEQ ID NO: 14); N-myristoyl-GAQFSKTAAK (SEQ ID NO: 15); N-myristoyl-GAQFSKTAA (SEQ ID NO: 16); N-myristoyl-GAQFSKTA (SEQ ID NO: 17); N-myristoyl-GAQFSKT (SEQ ID NO: 18); and N-myristoyl-GAQFSK (SEQ ID NO: 19). 4. The method according to claim 1, wherein said inflammatory cell is a leukocyte. 5. The method according to claim 1, wherein said inflammatory cell is a granulocyte. 6. The method according to claim 1, wherein said inflammatory cell is selected from the group consisting of a neutrophil, a basophil, an eosinophil and a combination thereof. 7. The method according to claim 1, wherein said inflammatory cell is a monocyte or macrophage. 8. The method according to claim 1, wherein said inflammatory mediator is selected from the group consisting of myeloperoxidase (MPO), eosinophil peroxidase (EPO), lysozyme, granzyme and a combination thereof. 9. The method according to claim 1, wherein said effective amount comprises a degranulation-inhibiting amount of an active fragment of MANS peptide that reduces the amount of an inflammatory mediator released from said inflammatory cell from about 1% to about 99% as compared to the amount released from said inflammatory cell in the absence of said active fragment. 10. The method according to claim 1, wherein said effective amount comprises a degranulation-inhibiting amount of an active fragment of MANS peptide that reduces the amount of an inflammatory mediator released from said inflammatory cell from between about 5-50% to about 99% as compared to the amount released from said inflammatory cell in the absence of said active fragment. 11. The method of claim 1, wherein the chronic inflammatory disease is selected from the group consisting of insulin-dependent diabetes mellitus, multiple sclerosis, Gullian-Barre syndrome, graft versus host disease, and systemic lupus erythematosus. 12. A method of inhibiting release of an inflammatory mediator associated with a chronic inflammatory disease in a subject comprising: administration to a tissue and/or fluid of said subject suffering from a chronic inflammatory disease, wherein said tissue and/or said fluid comprises at least one inflammatory cell comprising at least one inflammatory mediator contained within a granule inside the cell, a therapeutically effective amount of a pharmaceutical composition comprising at least one active myristoylated N-terminal fragment of a MANS peptide (SEQ ID NO:1), wherein said fragment comprises at least six contiguous amino acids of said MANS peptide, in a therapeutically effective amount to reduce the MARCKS-related release of said at least one inflammatory mediator from said inflammatory cell. 13. The method of claim 12, wherein said inflammatory mediator is selected from the group consisting of myeloperoxidase (MPO), eosinophil peroxidase (EPO), major basic protein (MBP), lysozyme, granzyme, histamine, proteoglycan, protease, a chemotactic factor, cytokine, a metabolite of arachidonic acid, defensin, bactericidal permeability-increasing protein (BPI), elastase, cathepsin G, cathepsin B, cathepsin D, beta-D-glucuronidase, alpha-mannosidase, phospholipase A.sub.2, chondroitin-4-sulphate, proteinase 3, lactoferrin, collagenase, complement activator, complement receptor, N-formylmethionyl-leucyl-phenylalanine (FMLP) receptor, laminin receptor, cytochrome b.sub.558, monocyte-chemotactic factor, histaminase, vitamin B12 binding protein, gelatinase, plasminogen activator, and a combination thereof. 14. The method according to claim 12, wherein said reducing the MARCKS-related release of said inflammatory mediator comprises blocking or inhibiting the mechanism that releases said inflammatory mediator from said inflammatory cell. 15. The method according to claim 12, wherein said active fragment can be selected from the group consisting of N-myristoyl-GAQFSKTAAKGEAAAERPGEAAV (SEQ ID NO: 20); N-myristoyl-GAQFSKTAAKGEAAAERPGEAA (SEQ ID NO: 3); N-myristoyl-GAQFSKTAAKGEAAAERPGEA (SEQ ID NO: 4); N-myristoyl-GAQFSKTAAKGEAAAERPGE (SEQ ID NO: 5); N-myristoyl-GAQFSKTAAKGEAAAERPG (SEQ ID NO: 6); N-myristoyl-GAQFSKTAAKGEAAAERP (SEQ ID NO: 7); N-myristoyl-GAQFSKTAAKGEAAAER (SEQ ID NO: 8); N-myristoyl-GAQFSKTAAKGEAAAE (SEQ ID NO: 9); N-myristoyl-GAQFSKTAAKGEAAA (SEQ ID NO: 10); N-myristoyl-GAQFSKTAAKGEAA (SEQ ID NO: 11); N-myristoyl-GAQFSKTAAKGEA (SEQ ID NO: 12); N-myristoyl-GAQFSKTAAKGE (SEQ ID NO: 13); N-myristoyl-GAQFSKTAAKG (SEQ ID NO: 14); N-myristoyl-GAQFSKTAAK (SEQ ID NO: 15); N-myristoyl-GAQFSKTAA (SEQ ID NO: 16); N-myristoyl-GAQFSKTA (SEQ ID NO: 17); N-myristoyl-GAQFSKT (SEQ ID NO: 18); and N-myristoyl-GAQFSK (SEQ ID NO: 19). 16. The method according to claim 12, wherein said inflammatory cell is a leukocyte. 17. The method according to claim 12, wherein said inflammatory cell is a granulocyte. 18. The method according to claim 12, wherein said inflammatory cell is selected from the group consisting of a neutrophil, a basophil, an eosinophil and a combination thereof. 19. The method according to claim 12, wherein said inflammatory cell is a monocyte or macrophage. 20. The method according to claim 12, wherein said inflammatory mediator is selected from the group consisting of myeloperoxidase (MPO), eosinophil peroxidase (EPO), lysozyme, granzyme and a combination thereof. 21. The method according to claim 12, wherein said effective amount comprises a degranulation-inhibiting amount of an active fragment of MANS peptide that reduces the amount of an inflammatory mediator released from said inflammatory cell from about 1% to about 99% as compared to the amount released from said inflammatory cell in the absence of said active fragment. 22. The method according to claim 12, wherein said effective amount comprises a degranulation-inhibiting amount of an active fragment of MANS peptide that reduces the amount of an inflammatory mediator released from said inflammatory cell from about 5 to 50% to about 99% as compared to the amount released from said inflammatory cell in the absence of said active fragment. 23. The method according to claim 12, wherein said chronic inflammatory disease is selected from the group consisting of insulin-dependent diabetes mellitus, multiple sclerosis, Gullian-Barre syndrome, graft versus host disease, and systemic lupus erythematosus. 24. The method according to claim 12, wherein said subject is a mammal. 25. The method according to claim 12, wherein said mammal is selected from the group consisting of a human, a canine, an equine and a feline. 26. The method according to claim 12, wherein said administration is selected from the group consisting of topical administration, parenteral administration, rectal administration, pulmonary administration, nasal administration, and oral administration. 27. The method according to claim 26, wherein said pulmonary administration is selected from the group of aerosol, dry powder inhaler, metered dose inhaler, and nebulizer. 28. The method according to claim 12, further comprising administration to said subject of a second molecule selected from the group consisting of an antibiotic, an antiviral compound, an antiparasitic compound, an anti-inflammatory compound, and an immunosuppressant.

Details for Patent 8,563,689

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2021-06-26
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2021-06-26