Interferon-beta fusion proteins and uses

• US 20050214253A1
• Filed: 06/15/2004
• Published: 09/29/2005
• Est. Priority Date: 10/16/1998
• Status: Active Grant

• Current Assignee: Biogen Idec MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.)
• Inventors: Brickelmaier, Margot, Hochman, Paula, Whitty, Adrian, Runkel, Laura
• Granted Patent: US 7,527,946 B2
• Time in Patent Office: Days
• US Class Current: 424/85.500
• 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: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• 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 31/12 Antivirals
• 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 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: C07K 14/565 IFN-beta
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

A fusion polypeptide is described having the amino acid sequence X-Y-Z, or portion thereof, comprising the amino acid sequence of a glycosylated interferon-beta (X); Y is an optional linker moiety; and Z is a polypeptide comprising at least a portion of a polypeptide other than glycosylated interferon-beta. It is preferred that X is human interferon-beta-1a. Mutants of interferon-beta-1a are also described.

Claims

1. An isolated polypeptide having the amino acid sequence X-Y-Z, wherein

X is a polypeptide having the amino acid sequence, or portion thereof, comprising the amino acid sequence of a glycosylated interferon-beta;

Y is an optional linker moiety; and

Z is a polypeptide comprising at least a portion of a polypeptide other than glycosylated interferon-beta.

2. The isolated polypeptide of claim 1, wherein X is interferon-beta-1a.

3. The isolated polypeptide of claim 1, wherein X is a mutant having at least one of the following properties:

(a) the mutant has a higher antiviral activity than wild type interferon beta 1a, wherein the antiviral activity is measured by viral induced lysis of cells;

(b) the mutant has, relative to wild type interferon-beta-1a, greater antiviral activity than antiproliferative activity;

(c) the mutant binds interferon receptor but has, when compared to wild type interferon-beta-1a, lowered antiviral activity and lowered antiproliferative activity relative to its receptor binding activity.

4. The isolated polypeptide of claim 2, wherein the interferon beta-1a is derivatized.

5. The isolated polypeptide of claim 4, wherein the derivative is a polyalkylglycol polymer.

6. The isolated polypeptide of claim 1, wherein Z is at least a portion of a constant region. of an immunoglobulin.

7. The isolated polypeptide of claim 6, wherein said at least a portion of the constant region is derived from an immunoglobulin of the class selected from classes IgM, IgG, IgD, IgA, and IgE.

8. The isolated polypeptide of claim 7, wherein the class is IgG.

9. The isolated polypeptide of claim 6, wherein the at least a portion of the constant region comprises at least a hinge, CH2 and CH3 domains.

19. An isolated DNA sequence encoding for the protein of claims 1 and 10.

20. A recombinant DNA comprising the DNA sequence of claim 19 and an expression control sequence, wherein the expression control sequence is operatively linked to the DNA.

21. A host cell transformed with the recombinant DNA sequence of claim 20.

22. A method of producing a recombinant polypeptide comprising:

(a) providing a population of host cells according to claim 21;

(b) growing said population of cells under conditions whereby the polypeptide encoded by said recombinant DNA is expressed; and

(c) isolating the expressed polypeptide.

26. A pharmaceutical composition comprising a therapeutically effective amount of the interferon beta fusion protein of claims 1, 10 and 23.

27. A method of inhibiting angiogenesis in a subject, comprising administering to a subject an effective amount of the composition of claim 26.

28. The isolated polypeptide of claim 3, wherein the mutant is derivatized.

29. The isolated polypeptide of claim 27, wherein the derivative is a polyalklyglycol polymer.

31. The isolated protein of claim 29, wherein the derivative is a polyalkylglycol polymer.

10. A fusion protein having an amino terminal region consisting of the amino acid sequence of a glycosylated interferon-beta or a portion thereof and having a carboxy terminal region comprising at least a portion of a protein other than glycosylated interferon-beta.

11. The isolated protein of claim 10, wherein X is interferon-beta-1a.

12. The isolated protein of claim 10, wherein X is a mutant having at least one of the following properties:

(a) the mutant has a higher antiviral activity than wild type inteferon beta 1a, wherein the antiviral activity is measured by viral induced lysis of cells;

(b) the mutant has, relative to wild type interferon-beta-1a, greater antiviral activity than antiproliferative activity;

(c) the mutant binds interferon receptor but has, compared to wild type interferon-beta-1a, lowered antiviral activity and lowered antiproliferative activity relative to its receptor binding activity.

13. The isolated protein of claim 11, wherein the interferon-beta-1a is derivatized.

14. The isolated protein of claim 13, wherein the derivative is a polyalkylglycol polymer.

15. The isolated protein of claim 10, wherein the at least a portion of the protein other than interferon beta is at least a portion of a constant region of an immunoglobulin.

16. The isolated protein of claim 15, wherein said at least a portion of the constant region is derived from an immunoglobulin of the class selected from classes IgM, IgG, IgD, IgA, and IgE.

17. The isolated protein of claim 16, wherein the class is IgG.

18. The isolated protein of claim 15, wherein the at least a portion of the constant region is comprises at least a hinge, CH2 and CH3 domains.

30. The isolated protein of claim 12, wherein the mutant is derivatized.

23. An interferon-beta fusion protein comprising a glycosylated interferon beta and additional polypeptide with which it is not natively associated, in substantially purified form

24. The fusion protein of claim 23, wherein said interferon beta is human interferon-beta-1a.

25. The fusion protein of claim 24, wherein said fusion has an antiviral activity that is selected from the group consisting of:

(a) a higher antiviral activity than wild type inteferon beta 1a, wherein the antiviral activity is measured by viral induced lysis of cells, (b) a greater antiviral activity than antiproliferative activity, relative to wild type interferon-beta-1a;

(c) an activity that includes receptor binding activity but, compared to wild type interferon-beta-1a, a lowered antiviral activity and lowered antiproliferative activity relative to said receptor binding activity.