Polymer conjugates of interferon beta-1a and uses

• US 6,962,978 B2
• Filed: 04/11/2001
• Issued: 11/08/2005
• Est. Priority Date: 10/16/1998
• Status: Expired due to Term

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen, Inc.
• Inventors: Brickelmaier, Margot, Hochman, Paula, Whitty, Adrian, Pepinsky, Blake, Runkel, Laura
• Primary Examiner(s): Kunz, Gary
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US09/832,658
• Publication Number:
  US 20030021765A1
• Time in Patent Office: 1,672 Days
• Field of Search: 530/351, 530/395, 530/402, 514/12, 424/85.6, 930/142
• US Class Current: 530/351
• 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. A composition comprising the glycosylated interferon-beta-1a of SEQ ID NO:

25 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.

2. The composition of claim 1, 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.

3. The composition of claim 1, wherein the interferon-beta-1a of SEQ ID NO:

25 is an inlerferon-beta-1a fusion protein.

4. The composition of claim 3, wherein the interferon-beta-1a fusion protein comprises a portion of an immunoglobulin molecule.

5. A composition comprising the glycosylated interferon-beta-1a of SEQ ED NO:

26 coupled to a non-naturally-occurring polymer at the N-terminus of said glycosylated interferon-beta-1a, said polymer comprising a polyalkylene glycol moiety.

6. The composition of claim 5, wherein the glycosylated interferon-beta-1a of SEQ ID NO:

26is an interferon-beta-1a fusion protein.

7. The composition of claim 6, wherein the interferon-beta-1a fusion protein comprises a portion of an immunoglobulin molecule.

8. A physiologically active interferon-beta composition comprising a physiologically active interferon-beta-1a comprising the amino acid sequence of SEQ ID NO:

25 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.

9. The composition of claim 8, wherein the interferon-beta-1a is coupled to the polymer at a site by way of a glycan moiety the interferon-beta-1a.

10. The composition of claim 8, wherein interferon-beta-1a is an interferon-beta-1a fusion protein.

11. The composition of claim 10, wherein the interferon-beta-1a fusion protein comprises a portion of an immunoglobulin molecule.

12. A physiologically active interferon-beta composition comprising a pysiologically active glycosylated interferon-beta-1a comprising the amino acid sequence of SEQ ID NO:

25 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.

13. The composition of claim 12, wherein the interferon-beta is coupled to the polymer at a site by way of a glycan moiety on the interferon-beta.

14. The composition of claim 12, wherein the interferon-beta-1a is an interferon beta fusion protein.

15. The composition of claim 14, wherein the interferon beta fusion protein comprises a portion of an immunoglobulin molecule.

17. A interferon-beta composition according to claims 12, or 16, wherein the polymer has a molecular weight of from about 5 to about 40 kilodaltons.

18. A pharmaceutical composition comprising the interferon-beta composition of claim 17.

16. A stable, aqueously soluble, conjugated interferon-beta-1a complex comprising a interferon-beta-1a comprising the amino acid sequence of SEQ ID NO:

25 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 proteolysis.

19. A physiologically active interferon-beta composition comprising a physiologically active interferon-beta-1a comprising the amino acid sequence of SEQ ID NO:

26 coupled to a non-naturally-occurring polymer at the N-terminus of said glycosylated interferon-beta-1a, said 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 an activity at least 2-fold greater relative to physiologically active interferon-beta-1b, when measured by an antiviral assay.

20. The composition of claim 19, wherein the interferon-beta-1a is an interferon-beta-1a fusion protein.

21. The composition of claim 20, wherein the interferon-beta-1a fusion protein comprises a portion of an immunoglobulin molecule.

22. A physiologically active interferon-beta composition comprising a physiologically active glycosylated interferon-beta-1a, comprising the amino acid sequence of SEQ ID NO:

25, 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 physiologicaily active interferon-beta lacking said moiety, when measured by an antiviral assay.

23. The composition of claim 22, wherein the interferon-beta-1a is an interferon beta fusion protein.

24. The composition of claim 23, wherein the interferon beta fusion protein comprises a portion of an immunoglobulin molecule.