Pharmaceutical compositions for treating arthritis and inflammatory disease

• US 20050090647A1
• Filed: 10/15/2004
• Published: 04/28/2005
• Est. Priority Date: 05/14/1998
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Gatanaga, Tetsuya, Granger, Gale A.
• Granted Patent: US 7,399,465 B2
• Time in Patent Office: Days
• US Class Current: 530/350
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/4705 stimulating, promoting or activating activity
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C12N 9/6421 from mammals
• CPC Class Codes: C12N 9/6489 Metalloendopeptidases (3.4.24)
• CPC Class Codes: G01N 2333/525 Tumor necrosis factor [TNF]
• CPC Class Codes: G01N 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors

Abstract

The biological effects of the cytokine TNF are mediated by binding to receptors on the surface of cells. This disclosure describes new proteins and polynucleotides that promote enzymatic cleavage and release of TNF receptors. Also provided are methods for identifying additional compounds that influence TNF receptor shedding. As the active ingredient in a pharmaceutical composition, the products of this invention increase or decrease TNF signal transduction, thereby alleviating the pathology of disease.

Claims

1-32. -32. (canceled)

33. An isolated protein comprising a consecutive amino acid sequence that is at least 90% identical to SEQ. ID NO:

9, or fragment thereof that causes cleavage of TNF receptor from human cells on which TNF receptor is expressed.

37. The isolated polypeptide of claim 33, which cleaves TNF receptor from the surface of cells.

38. The isolated polypeptide of claim 33, which causes release of the human p55 TNF receptor from cells expressing the receptor.

39. The isolated polypeptide of claim 33, which causes release of the human p75 TNF receptor from cells expressing the receptor.

40. A method of causing enzymatic release of TNF receptor from a cell, comprising contacting the cell with a polypeptide according to claim 33.

41. A method of reducing TNF signal transduction in a cell, comprising contacting the cell with a polypeptide according to claim 33.

42. A method for preparing a pharmaceutical composition, comprising compounding the protein of claim 33 in an excipient suitable for human administration.

43. The method of claim 33, comprising packaging the composition with instructions for using the composition to reduce inflammation.

44. The method of claim 33, comprising packaging the composition with instructions for using the composition to treat arthritis.

45. A pharmaceutical composition, comprising the polypeptide of claim 33, in a suitable excipient.

46. The pharmaceutical composition of claim 45, packaged with instructions for using it to reduce inflammation.

47. The pharmaceutical composition of claim 45, packaged with instructions for using it to treat arthritis.

48. A method for producing the polypeptide of claim 33, comprising expressing a polynucleotide comprising a sequence that is at least 90% identical to SEQ. ID NO:

9.

49. A method for producing an antibody specific for the protein of claim 33, comprising immunizing a mammal or contacting an immunocompetent cell or particle with the protein of claim 33, or an immunogenic fragment thereof.

50. An isolated antibody specific for the protein of claim 33.

51. An assay method for determining altered expression of the protein of claim 33 in a cell or tissue sample, comprising:

a) contacting the sample with the antibody of claim 50 under conditions that permit the antibody to bind the protein if present in the sample, thereby forming an antibody-antigen complex; and

b) determining any complex formed as a measure of altered expression of the protein.

34. An isolated polypeptide comprising an amino acid sequence encoded in a DNA that hybridizes to a DNA having the sequence of SEQ. ID NO:

9 at 30°

C. in 6×

SSC, wherein the protein causes cleavage of TNF receptor from human cells in which TNF receptor is expressed.

35. An isolated protein comprising a consecutive amino acid sequence that is at least 80% identical to SEQ. ID NO:

9, or fragment thereof that protects mice against septic shock caused by administration of an otherwise lethal dose of lipopolysaccharide (LPS).

52. A method for reducing arthritis or treating inflammation in a subject, comprising administering to the subject a protein according to claim 35.

36. An isolated polypeptide comprising an amino acid sequence encoded in a DNA that hybridizes to a DNA having the sequence of SEQ. ID NO:

9 at 30°

C. in 6×

SSC, wherein the protein protects mice against septic shock caused by administration of an otherwise lethal dose of LPS.