Methods of treating diabetes using therapeutic agents comprising a GLP-1 receptor agonist and elastin-like peptides

Patent metadata

Field	Value
Publication number	US-9200083-B2
Application number	US-201213445979-A
Country	US
Kind code	B2
Filing date	Apr 13, 2012
Priority date	Jun 27, 2008
Publication date	Dec 1, 2015
Grant date	Dec 1, 2015

Abstract

The present invention provides therapeutic agents and compositions comprising elastin-like peptides (ELPs) and therapeutic proteins. In some embodiments, the therapeutic protein is a GLP-1 receptor agonist, insulin, or Factor VII/VIIa, including functional analogs. The present invention further provides encoding polynucleotides, as well as methods of making and using the therapeutic agents. The therapeutic agents have improvements in relation to their use as therapeutics, including, inter alia, one or more of half-life, clearance and/or persistance in the body, solubility, and bioavailability.

First claim

What is claimed is:

1. A method of treating diabetes in a subject in need thereof, comprising administering an effective amount of a therapeutic agent,
wherein said therapeutic agent comprises an elastin-like peptide (ELP) and a glucagon-like peptide (GLP)-1 receptor agonist,
wherein the ELP comprises at least one repeating unit selected from SEQ ID NOs: 1-12.

2. The method of claim 1 , wherein the therapeutic agent is a fusion protein comprising a GLP-1 receptor agonist and ELP.

3. The method of claim 2 , wherein the GLP-1 receptor agonist is GLP-1 (7-37) or GLP-1 (7-36).

4. The method of claim 1 , wherein GLP-1 receptor agonist is GLP-1 (7-37) or GLP-1 (7-36) having from 1 to 3 amino acid modifications independently selected front an insertion, a deletion, a truncation, and/or a substitution.

5. The method of claim 4 , wherein the GLP-1 receptor agonist is GLP-1 (7-37) having an alanine to glycine substitution at position 8.

6. The method of claim 1 , wherein the GLP-1 receptor agonist is an exendin-4 or a functional analog having from 1 to 3 amino acid modifications independently selected from an insertion, a deletion, a truncation, and/or a substitution.

7. The method of claim 1 , wherein the GLP-1 receptor agonist corresponds to a peptide derived from processing of a pro-glucagon gene.

8. The method of claim 7 , wherein the GLP-1 receptor agonist is an oxyntomodulin.

9. The method of claim 1 , wherein the GLP-1 receptor agonist is positioned at the N-terminal side of the ELP.

10. The method of claim 1 , wherein said therapeutic agent further comprises a spacer moiety between the ELP and GLP-receptor agonist.

11. The method of claim 1 , wherein said repeating unit is VPGXG (SEQ ID NO: 3), and wherein X is any natural or non-natural amino acid residue.

12. The method of claim 11 , wherein each X is V, G, or A at a ratio of 5:3:2.

13. The method of claim 12 , wherein the ELP comprises 60 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V, G, or A at a ratio of 5:3:2.

14. The method of claim 12 , wherein the ELP comprises 90 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V, G, or A at a ratio of 5:3:2.

15. The method of claim 12 , wherein the ELP comprises 120 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V, G, or A at a ratio of 5:3:2.

16. The method of claim 12 , wherein the ELP comprises 180 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V, G, or A at a ratio of 5:3:2.

17. The method of claim 11 , wherein each X is K, V, or F at a ratio of 1:2:1.

18. The method of claim 17 , wherein the ELP comprises 32 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:2:1.

19. The method of claim 17 , wherein the ELP comprises 64 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:2:1.

20. The method of claim 11 , wherein each X is K, V, or F at a ratio of 1:7:1.

21. The method of claim 20 , wherein the ELP comprises 36 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:7:1.

22. The method of claim 20 , wherein the ELP comprises 72 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:7:1.

23. The method of claim 20 , wherein the ELP comprises 144 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:7:1.

24. The method of claim 11 , wherein each X is V.

25. The method of claim 24 , wherein the ELP comprises 60 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V.

26. The method of claim 24 , wherein the ELP comprises 120 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V.

27. The method of claim 1 , wherein said repeating unit is AVGVP (SEQ ID NO: 4).

28. The method of claim 27 , wherein the ELP comprises 30 repeats of AVGVP (SEQ ID NO: 4).

29. The method of claim 27 , wherein the ELP comprises 60 repeats of AVG VP (SEQ ID NO: 4).

30. The method of claim 1 , wherein said repeating unit is IPGXG (SEQ ID NO: 5), wherein X is V.

31. The method of claim 30 , wherein the ELP comprises 15 repeats of IPGXG (SEQ ID NO: 5), wherein X is V.

32. The method of claim 1 , wherein said repeating unit is LPGXG (SEQ ID NO: 7), wherein X is V.

33. The method of claim 32 , wherein the ELP comprises 30 repeats of LPGXG (SEQ ID NO: 5), wherein X is V.

34. The method of claim 32 , wherein the ELP comprises 60 repeats of LPGXG (SEQ ID NO: 5), wherein X is V.

35. The method of claim 1 , wherein the therapeutic agent has a molecular weight of less than about 60 kDa.

36. The method of claim 1 , wherein the ELP has a Tt of from about 35° C. to about 60° C.

37. The method of claim 1 , wherein the ELP has a Tt of about 35°C.

38. The method of claim 1 , wherein the therapeutic agent comprises amino acids 8 to 643 of SEQ ID NO: 56.

39. The method of claim 1 , wherein the therapeutic agent is administered with a pharmaceutically acceptable carrier and/or excipient.

40. A method of treating diabetes in a subject in need thereof, comprising administering an effective amount of a therapeutic agent, said therapeutic agent comprising an elastin-like peptide (ELP) and a glucagon-like peptide (GLP)-1 receptor agonist positioned at the N-terminal side of the ELP component, wherein the ELP:
(i) comprises 60 repeats of VPGXG (SEQ ID NO: 3), where each X is V, G, or A at a ratio of 5:3:2;
(ii) comprises 32 repeats of VPGXG (SEQ ID NO: 3), where each X is K, V, or F at a ratio of 1:2:1;
(iii) comprises 36 repeats of VPGXG (SEQ ID NO: 3), where each X is K, V, or F at a ratio of 1:7:1,
(iv) comprises 60repeats of VPGXG (SEQ ID NO: 3), where X is V,
(v) comprises 30 repeats of VPGXG (SEQ ID NO: 4),
(vi) comprises 15 repeats of VPGXG (SEQ ID NO: 5), where X is V, or
(vii) comprises 30 repeats of VPGXG (SEQ ID NO: 7), where X is V.

41. The method of claim 40 , wherein the ELP comprises at least 90 repeats of VPGXG (SEQ ID NO: 3), where each X is V, G, or A at a ratio of 5:3:2.

Assignees

• Chilkoti Ashutosh
• Univ Duke

Inventors

• Chilkoti Ashutosh

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title