Modified transferrin fusion proteins

1. A fusion protein comprising a transferrin (Tf) protein fused to a glucagon-like peptide-1 (GLP-1).

2. The fusion protein of claim 1 , wherein the serum half-life of the GLP-1 peptide is increased over the serum half-life of a GLP-1 peptide in an unfused state.

3. The fusion protein of claim 1 , wherein the GLP-1 peptide is GLP-1(7–36) or GLP-1(7–37).

4. The fusion protein of claim 3 , wherein the GLP-1 peptide is GLP-1(7–37) consisting of SEQ ID NO: 6 or is GLP-1(7–36) consisting of amino acids 1–30 of SEQ ID NO: 6.

5. The fusion protein of claim 4 , wherein the GLP-1 peptide has been modified by mutating Ala at position 2 in SEQ ID NO: 6.

6. The fusion protein of claim 5 , wherein Ala at position 2 in SEQ ID NO: 6 has been mutated to Gly, Ser, or Val.

7. The fusion protein of claim 4 , wherein the GLP-1 peptide has been modified by mutating Lys at position 28 in SEQ ID NO: 6.

8. The fusion protein of claim 7 , wherein Lys at position 28 in SEQ ID NO: 6 has been mutated to Ala, Asn, or Gin.

9. The fusion protein of claim 4 , wherein the GLP-1 peptide has been modified by mutating Ala at position 2 in SEQ ID NO: 6 to Gly and Lys at position 28 in SEQ ID NO: 6 to Ala.

10. The fusion protein of claim 1 , wherein the GLP-1 peptide consists of the sequence: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQ ID NO: 6).

11. The fusion protein of claim 1 , wherein GLP-1 has been modified to prevent dipeptidyl peptidase cleavage.

12. The fusion protein of claim 11 , wherein GLP-1 has been modified at the N-terminus.

13. The fusion protein of claim 12 , wherein GLP-1 has been chemically modified at the N-terminus.

14. The fusion protein of claim 13 , wherein the His at the N-terminus of GLP-1 has been chemically modified.

15. The fusion protein of claim 1 , wherein the GLP-1 peptide is fused to the N-terminal end of the Tf protein.

16. The fusion protein of claim 1 , wherein the transferrin (Tf) protein exhibits reduced glycosylation as compared to a fully glycosylated Tf protein.

17. The fusion protein of claim 16 , wherein the Tf protein comprises at least one mutation that prevents glycosylation.

18. The fusion protein of claim 17 , wherein the mutation is in an N-linked glycosylation site comprising the sequence N-X-S/T.

19. The fusion protein of claim 18 , wherein the Tf protein has been modified to have no affinity for iron.

20. The fusion protein of claim 18 , wherein the sequence N-X-S/T sequence begins at an amino acid corresponding to N413 or N611 of SEQ ID NO: 3.

21. The fusion protein of claim 20 , wherein N, X, S, or T has been changed to a proline.

22. The fusion protein of claim 1 , wherein the Tf protein has been modified to exhibit no glycosylation.

23. The fusion protein of claim 1 , wherein the Tf protein has been further modified to have reduced affinity for a transferrin receptor (TfR) as compared to a wild-type Tf protein.

24. The fusion protein of claim 23 , wherein the Tf protein has been modified to have no binding for a TfR.

25. The fusion protein of claim 1 , wherein the Tf protein has been further modified to have reduced affinity for iron as compared to a wild-type Tf protein.

26. The fusion protein of claim 1 , wherein the fusion protein further comprises a linker.

27. The fusion protein of claim 26 , wherein the linker links the GLP-1 peptide to the Tf protein.

28. The fusion protein of claim 1 , wherein the Tf protein comprises a portion of the N domain of a Tf protein, a bridging peptide, and a portion of the C domain of a Tf protein.

29. The fusion protein of claim 1 , wherein the Tf protein is a human protein.

30. The fusion protein of claim 29 , wherein the Tf protein comprises SEQ ID NO: 3.

31. A modified Tf fusion protein comprising a Tf protein exhibiting reduced N-linked glycosylation fused at its N-terminus to a GLP-1 moiety comprising the sequence: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Ala-Gly-Arg-Gly (SEQ ID NO: 67).

32. A pharmaceutical composition comprising the fusion protein of any one of claims 1 – 31 and a carrier.

33. A fusion protein comprising a GLP-1 peptide fused at its C-terminus to the N-terminus of a Tf protein which exhibits reduced N-linked glycosylation as compared to a fully N-linked glycosylated Tf protein, wherein the serum half-life of the GLP-1 peptide is increased compared to the serum half-life of a GLP-1 peptide in an unfused state.

34. A fusion protein of claim 33 , wherein the Tf protein lacks N-linked glycosylation.

35. A composition comprising a fusion protein of claim 33 or 34 .

36. A composition of claim 35 , wherein the composition is a pharmaceutical composition.

37. A fusion protein comprising lactoferrin or melanotransferrin protein fused to a glucagon-like peptide- 1 (GLP- 1 ).

38. A method of treating a disease or condition treatable by GLP-1 in a subject comprising administering to said subject a therapeutically effective amount of a fusion protein of claim 1 .

39. The method of claim 38 , wherein the disease is a metabolic disease.

40. The method of claim 39 , wherein the metabolic disease is diabetes or obesity.

41. The method of claim 40 , wherein the diabetes is type II diabetes.

42. The method of claim 38 , wherein the disease is congestive heart failure.

43. The method of claim 38 , wherein the disease is inflammatory bowel syndrome disease.

44. The method of claim 38 , wherein the subject is suffering from elevated level of glucose as compared to a healthy subject.

45. A method of claim 38 , wherein the elevated level of glucose is associated with diabetes.

46. A method of claim 45 , wherein the diabetes is Type II diabetes.

47. A method of regulating glucose levels in a subject comprising administering to the subject a therapeutically effective amount of a fusion protein of claim 1 .