Polymer conjugates of interferon Beta-1a and uses

• US 20090104150A1
• Filed: 03/20/2008
• Published: 04/23/2009
• Est. Priority Date: 10/16/1998
• Status: Abandoned Application

• Current Assignee: Adrian Whitty, Blake Pepinsky, Laura Runkel, Margot Brickelmaier, Paula Hochman
• Original Assignee: Adrian Whitty, Blake Pepinsky, Laura Runkel, Margot Brickelmaier, Paula Hochman
• Inventors: Brickelmaier, Margot, Hochman, Paula, Whitty, Adrian, Pepinsky, Blake, Runkel, Laura
• Application Number:
  US12/077,605
• Publication Number:
  US 20090104150A1
• Time in Patent Office: Days
• US Class Current: 424/85.600
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y10S 930/142 : Interferon

Abstract

An interferon beta polypeptide comprising interferon-beta 1a coupled to a polymer containing a polyalkylene glycol moiety wherein the interferon-beta-1a and the polyalkylene glycol moiety are arranged such that the interferon-beta-1a has an enhanced activity relative to another therapeutic form of interferon beta (interferon-beta-1b) and exhibits no decrease in activity as compared to non-conjugated interferon-beta-1a. The conjugates of the invention are usefully employed in therapeutic as well as non-therapeutic, e.g., diagnostic, applications.

Claims

1-40. -40. (canceled)

41. A composition comprising a glycosylated interferon-beta-1a comprising the amino acid sequence set forth in any one of SEQ ID NOs:

27-39 and 42-56 coupled to a non-naturally-occurring polymer at an N-terminal end of said glycosylated interferon-beta-1a, said polymer comprising a polyalkylene glycol moiety.

42. The composition of claim 41, wherein the polyalkylene moiety is coupled to the interferon-beta by way of a group selected from an aldehyde group, a maleimide group, a vinylsulfone group, a haloacetate group, plurality of histidine residues, a hydrazine group and an aminothiol group.

43. The composition of claim 41, wherein the interferon-beta-1a of any one of SEQ ID NOs:

27-39 and 42-56 is an interferon-beta-1a fusion protein.

44. The composition of claim 43, wherein the interferon-beta-1a fusion protein comprises a portion of an immunoglobulin molecule.

54. An interferon-beta composition according to claim 41, wherein the polymer has a molecular weight of from about 5 to 40 kilodaltons.

57. A pharmaceutical composition comprising the interferon-beta composition of claim 54.

45. A physiologically active interferon-beta composition comprising a physiologically active interferon-beta-1a comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

27-39 and 42-56, coupled to a polymer comprising a polyalkylene glycol moiety, wherein the interferon-beta-1a is coupled to the polymer at a site on the interferon-beta-1a that is an N-terminal end, wherein the physiologically active interferon-beta-1a and the polyalkylene glycol moiety are arranged such that the physiologically active interferon-beta-1a in the physiologically active interferon-beta composition has an activity at least 2-fold greater relative to physiologically active interferon-beta-1b, when measured by an antiviral assay.

46. The composition of claim 45, wherein the interferon-beta-1a is coupled to the polymer at a site by way of a glycan moiety of the interferon-beta-1a.

47. The composition of claim 45, wherein the interferon-beta-1a is an interferon-beta-1a fusion protein.

48. The composition of claim 47, wherein the interferon-beta-1a fusion protein comprises a portion of an immunoglobulin molecule.

49. A physiologically active interferon-beta composition comprising a physiologically active glycosylated interferon-beta-1a comprising an amino acid sequence selected from the group consisting of SEQ ID NO:

27-39 and 42-56, N-terminally coupled to a polymer comprising a polyalkylene glycol moiety, wherein the physiologically active interferon-beta-1a and the polyalkylene glycol moiety are arranged such that the physiologically active interferon-beta 1a in the physiologically active interferon-beta composition has equal activity relative to physiologically active interferon-beta lacking said moiety, when measured by an antiviral assay.

50. The composition of claim 49, wherein the interferon-beta is coupled to the polymer at a site by way of a glycan moiety on the interferon-beta.

51. The composition of claim 49, wherein the interferon-beta-1a is an interferon beta fusion protein.

52. The composition of claim 51, wherein the interferon beta fusion protein comprises a portion of an immunoglobulin molecule.

55. An interferon-beta composition according to claim 49, wherein the polymer has a molecular weight of from about 5 to 40 kilodaltons.

53. A stable, aqueously soluble, conjugated interferon-beta-1a complex comprising a interferon-beta-1a comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

27-40 and 42-56 N-terminally coupled to a polyethylene glycol moiety, wherein the interferon-beta-1a is coupled to the polyethylene glycol moiety by a labile bond, wherein the labile bond is cleavable by biochemical hydrolysis and/or protcolysis.

56. A interferon-beta composition according to claim 53, wherein the polymer has a molecular weight of from about 5 to 40 kilodaltons.

58. A protein comprising the amino acid sequence set forth in any one of SEQ ID NOs:

25-56, coupled to a non-naturally-occurring polymer at the C-terminal end of said protein, said polymer comprising a polyalkylene glycol moiety.

59. A protein comprising the amino acid sequence set forth in any one of SEQ ID NOs:

25-56, coupled to a non-naturally-occurring polymer, said polymer comprising a polyalkylene glycol moiety, and said polymer is attached to an amino, carboxylic, hydroxyl, guanidyl, or glycan moiety of said protein.

60. A protein comprising the amino acid sequence set forth in any one of SEQ ID NOs:

25-56, coupled to a non-naturally-occurring polymer at the N-terminal end of said protein, said polymer comprising a polyalkylene glycol moiety.

62. A method of preparing the protein of claim 60, comprising reacting a protein with a non-naturally-occurring polymer under reductive alkylation conditions, said protein comprising the amino acid sequence set forth in any one of SEQ ID NOs:

25-56, and said polymer comprising a polyalkylene glycol moiety and a terminal aldehyde moiety.

61. A method of treating multiple sclerosis in a subject comprising administering to a subject in need thereof a therapeutically effect amount of a protein comprising the amino acid sequence set forth in any one of SEQ ID NOs:

25-56 coupled to a non-naturally-occurring polymer, said polymer comprising a polyalkylene glycol moiety.