Polymer conjugates of interferon beta-1A and uses

• US 7,446,173 B2
• Filed: 03/16/2004
• Issued: 11/04/2008
• Est. Priority Date: 10/16/1998
• Status: Expired due to Term

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.)
• Inventors: Brickelmaier, Margot, Hochman, Paula, Whitty, Adrian, Pepinsky, Blake, Runkel, Laura
• Primary Examiner(s): Bunner; Bridget E
• Assistant Examiner(s): Hamud; Fozia M
• Application Number:
  US10/802,540
• Publication Number:
  US 20070098688A1
• Time in Patent Office: 1,694 Days
• Field of Search: None
• 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 a glycosylated interferon-beta-1a comprising the amino acid sequence set forth in SEQ ID NO:

41, coupled to a non-naturally-occurring polymer at the 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 said 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:

41, is an interferon-beta-1a fusion protein.

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

14. An interferon-beta composition according to claim 1, wherein the polymer has a molecular weight of from about 5 to 40 kilodaltons.

17. A pharmaceutical composition comprising the interferon-beta composition of claim 14.

21. An interferon-beta composition according to claim 1, wherein the polymer has a molecular weight of about 20 kilodaltons.

25. An interferon-beta composition according to claim 1, wherein the polymer has a molecular weight of about 5 kilodaltons.

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

41, 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 the 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.

6. The composition of claim 5, wherein the interferon-beta-1a is coupled to the polymer by way of a glycan moiety of the interferon-beta-1a.

7. The composition of claim 5, wherein the interferon-beta-1a is an interferon-beta-1a fusion protein.

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

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

22. An interferon-beta composition according to claim 5, wherein the polymer has a molecular weight of about 20 kilodaltons.

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

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

41, 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.

10. The composition of claim 9, wherein the interferon-beta is coupled to the polymer by way of a glycan moiety on the interferon-beta.

11. The composition of claim 9, wherein the interferon-beta-1a is an interferon-beta fusion protein.

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

15. An interferon-beta composition according to claim 9, wherein the polymer has a molecular weight of from about 5 to 40 kilodaltons.

23. An interferon-beta composition according to claim 9, wherein the polymer has a molecular weight of about 20 kilodaltons.

27. An interferon-beta composition according to claim 9, wherein the polymer has a molecular weight of about 5 kilodaltons.

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

41, 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.

16. An interferon-beta composition according to claim 13, wherein the polymer has a molecular weight of from about 5 to 40 kilodaltons.

24. An interferon-beta composition according to claim 13, wherein the polymer has a molecular weight of about 20 kilodaltons.

28. An interferon-beta composition according to claim 13, wherein the polymer has a molecular weight of about 5 kilodaltons.

18. A protein comprising the amino acid sequence set forth in SEQ ID NO:

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

19. A method of preparing the protein of claim 18, comprising reacting a protein with a non-naturally-occurring polymer under reductive alkylation conditions, said protein comprising the amino acid sequence set forth in SEQ ID NO:

41, and said polymer comprising a polyalkylene glycol moiety and a terminal aldehyde moiety.