Albumin fusion proteins comprising GLP-1 polypeptides

• US 7,141,547 B2
• Filed: 02/11/2004
• Issued: 11/28/2006
• Est. Priority Date: 12/21/2001
• Status: Active Grant

• Current Assignee: Human Genome Sciences Incorporated (GSK plc), Novozymes Biopharma DK A/S (Novozymes)
• Original Assignee: Human Genome Sciences Incorporated (GSK plc)
• Inventors: Turner, Andrew J., Rosen, Craig A., Haseltine, William A., Ruben, Steven M., Ballance, David J.
• Primary Examiner(s): Wax, Robert A.
• Application Number:
  US10/775,204
• Publication Number:
  US 20050186664A1
• Time in Patent Office: 1,021 Days
• Field of Search: 514/12, 530/350
• US Class Current: 514/6.9
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
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• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
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• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
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• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/06 : of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
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• CPC Class Codes: A61P 9/06 : Antiarrhythmics
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• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/005 : from viruses
• CPC Class Codes: C07K 14/435 : from animals; from humans
• CPC Class Codes: C07K 14/4713 : Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
• CPC Class Codes: C07K 14/4723 : Cationic antimicrobial peptides, e.g. defensins
• CPC Class Codes: C07K 14/475 : Growth factors; Growth regulators
• CPC Class Codes: C07K 14/50 : Fibroblast growth factor [FGF]
• CPC Class Codes: C07K 14/505 : Erythropoietin [EPO]
• CPC Class Codes: C07K 14/51 : Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: C07K 14/521 : Chemokines
• CPC Class Codes: C07K 14/525 : Tumour necrosis factor [TNF]
• CPC Class Codes: C07K 14/535 : Granulocyte CSF; Granulocyte-macrophage CSF
• CPC Class Codes: C07K 14/54 : Interleukins [IL]
• CPC Class Codes: C07K 14/5406 : IL-4
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• CPC Class Codes: C07K 14/555 : Interferons [IFN]
• CPC Class Codes: C07K 14/56 : IFN-alpha
• CPC Class Codes: C07K 14/565 : IFN-beta
• CPC Class Codes: C07K 14/575 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/57563 : Vasoactive intestinal peptide [VIP]; Related peptides
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• CPC Class Codes: C07K 14/59 : Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• CPC Class Codes: C07K 14/60 : Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: C07K 14/605 : Glucagons
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• CPC Class Codes: C07K 14/635 : Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: C07K 14/65 : Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
• CPC Class Codes: C07K 14/655 : Somatostatins
• CPC Class Codes: C07K 14/665 : derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
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• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/20 : containing a tag with affinity for a non-protein ligand
• 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
• CPC Class Codes: C07K 2319/31 : fusions, other than Fc, for prolonged plasma life, e.g. albumin
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: C12N 15/62 : DNA sequences coding for fusion proteins
• CPC Class Codes: C12N 2501/335 : Glucagon; Glucagon-like peptide [GLP]; Exendin
• CPC Class Codes: C12N 2740/16111 : concerning HIV env
• CPC Class Codes: C12N 2740/16122 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: C12N 9/0006 : acting on CH-OH groups as donors (1.1)
• CPC Class Codes: C12N 9/0008 : acting on the aldehyde or oxo group of donors (1.2)
• CPC Class Codes: C12Y 101/01105 : Retinol dehydrogenase (1.1.1.105)
• CPC Class Codes: C12Y 102/01 : with NAD+ or NADP+ as acceptor (1.2.1)
• CPC Class Codes: C12Y 207/01095 : Kanamycin kinase (2.7.1.95), i.e. neomycin-kanamycin phosphotransferase

Abstract

The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disordrs or conditions using albumin fusion proteins of the invention.

Claims

1. An albumin fusion protein comprising two or more tandemly oriented GLP-1 polypeptides, wherein said GLP-1 polypeptides are selected from wild-type GLP-1, GLP-1 fragments, and GLP-1 variants, fused to albumin comprising the amino acid sequence of SEQ ID NO:

1038, an albumin fragment, or albumin variant thereof, wherein said albumin fragment or albumin variant increases the serum plasma half-life of the GLP-1 polypeptides, and wherein said fusion protein has GLP-1 activity.

2. The albumin fusion protein of claim 1, wherein said tandemly oriented GLP-1 polypeptides are selected from wild type GLP-1 sequences.

3. The albumin fusion protein of claim 1, wherein said tandemly oriented GLP-1 polypeptides are selected from GLP-1 fragment sequences.

4. The albumin fusion protein of claim 1, wherein said tandemly oriented GLP-1 polypeptides are selected from GLP-1 variant sequences.

5. The albumin fusion protein of claim 1, wherein said tandemly oriented GLP-1 polypeptides are selected from at least one wild type GLP-1 sequence fused to at least one GLP-1 fragment sequence.

6. The albumin fusion protein of claim 1, wherein said tandemly oriented GLP-1 polypeptides are selected from at least one wild type GLP-1 sequence fused to at least one GLP-1 variant sequence.

7. The albumin fusion protein of claim 1, wherein said tandemly oriented GLP-1 polypeptides are selected from at least one GLP-1 fragment sequence fused to at least one GLP-1 variant sequence.

8. The albumin fusion protein of claim 1, wherein said GLP-1 fragments or GLP-1 variants are selected from:

a. GLP-1(9-36);

b. GLP-1(7-36);

c. GLP-1(7-36(A8G)); and

d. GLP-1(7-36(A8S)).

9. The albumin fusion protein of claim 8, wherein said GLP-1 fragments or GLP-1 variants are selected from two tandemly oriented GLP-1(7-36(A8G)).

10. The albumin fusion protein of claim 9, wherein said two tandemly oriented GLP-1(7-36(A8G)) are fused at the N-terminus to albumin.

11. The albumin fusion protein of claim 9, wherein said two tandemly oriented GLP-1(7-36(A8G)) are fused at the C-terminus to albumin.

12. The albumin fusion protein of claim 1, wherein said tandemly oriented GLP-1 polypeptides are fused at the N-terminus to albumin.

13. The albumin fusion protein of claim 1, wherein said tandemly oriented GLP-1 polypeptides are fused at the C-terminus to albumin.

14. The albumin fusion protein of claim 1, produced from a host cell comprising a construct which expresses said albumin fusion protein, wherein said construct is selected from:

a. 2900;

b. 2964;

c. 2803;

d. 2804;

e. 2945;

f. 2982;

g. 3070;

h. 3027;

i. 3028;

j. 3045;

k. 3046;

l. 3069;

m. 3071;

n. 3072;

o. 3085;

p. 3086;

q. 3087;

r. 3309; and

s. 2904.

15. The albumin fusion protein of claim 1, which is non-glycosylated.

16. The albumin fusion protein of claim 1, which is expressed in yeast.

17. The albumin fusion protein of claim 16, wherein said yeast is a S. cerevisiae.

18. The albumin fusion protein of claim 16, wherein said yeast is glycosylation deficient.

19. The albumin fusion protein of claim 16, wherein said yeast is glycosylation and protease deficient.

20. The albumin fusion protein of claim 1, which is expressed by a mammalian cell.

21. The albumin fusion protein of claim 20, wherein said mammalian cell is a CHO cell.

22. The albumin fusion protein of claim 1, wherein the albumin fusion protein further comprises a secretion leader sequence.

23. A composition comprising the albumin fusion protein of claim 1 and a pharmaceutically acceptable carrier.

24. A method of treating a patient with diabetes, comprising administering an effective amount of the albumin fusion protein of claim 1.

25. An albumin fusion protein comprising two or more tandemly oriented GLP-1 polypeptides fused to albumin comprising the amino acid sequence of SEQ ID NO:

1038, wherein said GLP-1 polypeptides comprise at least one amino acid sequence selected from;

(a) amino acids 1 to 30 of SEQ ID NO;

1808;

(b) amino acids 100 to 127 of SEQ ID NO;

1249; and

(c) amino acids 98 to 127 of SEQ ID NO;

1250;

wherein said fusion protein has GLP-1 activity.

26. The albumin fusion protein of claim 25, wherein said GLP-1 polypeptides comprise at least one amino acid sequence of (a).

27. The albumin fusion protein of claim 26, wherein said GLP-1 polypeptides comprise at least two amino acid sequences of (a).

28. The albumin fusion protein of claim 25, wherein said GLP-1 polypeptides comprise at least one amino acid sequence of (b).

29. The albumin fusion protein of claim 28, wherein said GLP-1 polypeptides comprise at least two amino acid sequences of (b).

30. The albumin fusion protein of claim 25, wherein said GLP-1 polypeptides comprise at least one amino acid sequence of (c).

31. The albumin fusion protein of claim 30, wherein said GLP-1 polypeptides comprise at least two amino acid sequences of (c).

32. The albumin fusion protein of claim 25, wherein said GLP-1 polypeptides comprise at least one amino acid sequence of (a) and at least one amino sequence of (b).

33. The albumin fusion protein of claim 25, wherein said GLP-1 polypeptides comprise at least one amino acid sequence of (b) and at least one amino acid sequence of (c).

34. The albumin fusion protein of claim 25, wherein said GLP-1 polypeptides comprise at least one amino acid sequence of (a) and at least one amino acid sequence of (c).

35. The albumin fusion protein of claim 25, wherein said GLP-1 polypeptides are fused at the N-terminus to albumin.

36. The albumin fusion protein of claim 25, wherein said GLP-1 polypeptides are fused at the C-terminus to albumin.

37. The albumin fusion protein of claim 25, which is non-glycosylated.

38. The albumin fusion protein of claim 25, which is expressed in yeast.

39. The albumin fusion protein of claim 38, wherein said yeast is S. cerevisiae.

40. The albumin fusion protein of claim 38, wherein said yeast is glycosylation deficient.

41. The albumin fusion protein of claim 38, wherein said yeast is glycosylation and protease deficient.

42. The albumin fusion protein of claim 25, wherein the albumin fusion protein further comprises a secretion leader sequence.

43. A composition comprising the albumin fusion protein of claim 25 and a pharmaceutically acceptable carrier.

44. A method of treating a patient with diabetes, comprising administering an effective amount of the albumin fusion protein of claim 25.

45. An albumin fusion protein comprising two or more tandemly oriented GLP-1 polypeptides fused to human serum albumin, wherein said albumin fusion protein comprises an amino acid sequence selected from:

(a) amino acids 25 to 669 of SEQ ID NO;

1231;

(b) amino acids 25 to 669 of SEQ ID NO;

1232;

(c) amino acids 25 to 669 of SEQ ID NO;

1233;

(d) amino acids 25 to 667 of SEQ ID NO;

1234;

(e) amino acids 25 to 669 of SEQ ID NO;

1235;

(f) amino acids 25 to 669 of SEQ ID NO;

1236;

(g) amino acids 25 to 667 of SEQ ID NO;

1237;

(h) amino acids 30 to 674 of SEQ ID NO;

1280;

(i) amino acids 20 to 664 of SEQ ID NO;

1607;

(j) amino acids 20 to 664 of SEQ ID NO;

1608;

(k) amino acids 19 to 663 of SEQ ID NO;

1609;

(l) amino acids 19 to 663 of SEQ ID NO;

1610;

(m) amino acids 24 to 668 of SEQ ID NO;

1621;

(n) amino acids 86 to 730 of SEQ ID NO;

1622;

(o) amino acids 18 to 662 of SEQ ID NO;

1623;

(p) amino acids 86 to 730 of SEQ ID NO;

1624;

(q) amino acids 24 to 668 of SEQ ID NO;

1625;

(r) amino acids 18 to 662 of SEQ ID NO;

1626; and

(s) amino acids 30 to 673 of SEQ ID NO;

2170;

and wherein said fusion protein has GLP-1 activity.

46. The albumin fusion protein of claim 45, wherein said albumin fusion protein comprises the amino acid sequence of (h).

47. The albumin fusion protein of claim 45, wherein said albumin fusion protein further comprises a secretion leader sequence.

48. The albumin fusion protein of claim 45, which is glycosylated.

49. The albumin fusion protein of claim 45, which is expressed in yeast.

50. The albumin fusion protein of claim 49, wherein said yeast is S. cerevisiae.

51. The albumin fusion protein of claim 49, wherein said yeast is glycosylation deficient.

52. The albumin fusion protein of claim 49, wherein said yeast is glycosylation and protease deficient.

53. A composition comprising the albumin fusion protein of claim 45 and a pharmaceutically acceptable carrier.

54. A method of treating a patient with diabetes, comprising administering an effective amount of the albumin fusion protein of claim 45.

55. An albumin fusion protein comprising two or more tandemly oriented GLP-1 polypeptides fused to albumin, wherein said fusion protein is produced from a host cell comprising the amino acid sequence of the 3070 construct contained in ATCC Deposit No. PTA-4671.

56. A composition comprising the albumin fusion protein of claim 55 and a pharmaceutically acceptable carrier.

57. A method of treating a patient with diabetes, comprising administering an effective amount of the albumin fusion protein of claim 55.