GLUCAGON ANALOGS EXHIBITING PHYSIOLOGICAL SOLUBILITY AND STABILITY

• US 20090137456A1
• Filed: 11/06/2006
• Published: 05/28/2009
• Est. Priority Date: 11/07/2005
• Status: Active Grant

• Current Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Original Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Inventors: Dimarchi, Richard D., Smiley, David L.
• Granted Patent: US 8,338,368 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: Y02E 50/10 Biofuels, e.g. bio-diesel

Abstract

Modified glucagon peptides are disclosed having improved solubility and stability, wherein the native glucagon peptide has been modified by pegylation, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or both.

Claims

1. A glucagon peptide, wherein the side chain of one or two amino acid residues at positions 16, 17, 20, 21, 24, and/or 29, of said glucagon peptide further comprises a hydrophilic moiety covalently bound to the amino acid residue, and pharmaceutically acceptable salts of said glucagon peptide.

4. The glucagon peptide of claim 1, wherein said hydrophilic moiety is polyethylene glycol.

7. The glucagon peptide of claim 4 wherein the polyethylene glycol chain has a molecular weight selected from the range of about 1,000 to about 5,000 Daltons.

8. The glucagon peptide of claim 4 wherein the polyethylene glycol chain has a molecular weight greater than about 5,000 Daltons.

9. The glucagon peptide of claim 8 wherein amino acid 29 of the glucagon peptide is covalently bound to a second peptide comprising a sequence selected from the group consisting of SEQ ID NO:

19, SEQ ID NO;

20 and SEQ ID NO;

21.

11. The glucagon peptide of claim 1 wherein the glucagon peptide is selected from the group consisting of SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

10, SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, SEQ ID NO;

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18 and SEQ ID NO;

45.

14. The glucagon peptide of claim 9 wherein the second peptide is SEQ ID NO:

19 and the terminal amino acid of the glucagon peptide comprises an amide group in place of the carboxylic acid group of the native amino acid.

18. A multimer comprising at least two glucagon peptides of claim 1 bound to one another through a linker.

29. A pharmaceutical composition comprising a glucagon peptide of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. A kit for administering a glucagon agonist to a patient in need thereof, said kit comprising a pharmaceutical composition of claim 29;

and a device for administering said composition to a patient.

37. A method of treating hypoglycemia in a patient, said method comprising the steps of administering an effective amount of a pharmaceutical composition of claim 29 to the patient.

39. A method of causing temporary paralysis of the intestinal tract in a patient, said method comprising administering an effective amount of a pharmaceutical composition of claim 29 to the patient.

41. A method of reducing weight gain or inducing weight loss in a patient, said method comprising administering an effective amount of the pharmaceutical composition of claim 29 to the patient.

47. The method of claim 41 wherein amino acid 29 of the glucagon peptide is bound to a second peptide through a peptide bond, and said second peptide comprises sequence selected from the group consisting of SEQ ID NO:

19, SEQ ID NO;

20 and SEQ ID NO;

21.

48. The glucagon peptide of claim 1, wherein the side chain of an amino acid residue at position 21 and/or 24 comprises a hydrophilic moiety.

49. The glucagon peptide of claim 1 or 48, wherein the amino acid residue comprising the hydrophilic moiety is an amino acid selected from the group consisting of lysine, cysteine, ornithine, homocysteine, and acetyl phenylalanine.

50. The glucagon peptide of claims 1, 8, 9, 14, or 48, wherein the glucagon peptide comprises SEQ ID NO:

1 with one, two, or three amino acid substitutions at position(s) 2, 5, 7, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 27, 28, and/or 29.

51. The glucagon peptide of claim 1, wherein the glucagon peptide comprises SEQ ID NO:

1 with an amino acid substitution at position 12 and/or position 27.

52. The glucagon peptide of claim 1, wherein the glucagon peptide comprises an Arg at position 12 and/or a Leu or Norleucine at position 27.

53. The glucagon peptide of claim 1, wherein the C-terminal amino acid of the glucagon peptide comprises an amide group in place of the carboxylic acid group of the native amino acid.

54. The glucagon peptide of claim 1 or 11, wherein amino acid 29 of the glucagon peptide is covalently bound to a second peptide comprising a sequence selected from the group consisting of SEQ ID NO:

19, SEQ ID NO;

20 and SEQ ID NO;

21.

55. The glucagon peptide of claim 11, wherein the hydrophilic moiety is a polyethylene glycol having a molecular weight greater than about 5,000 Daltons.

56. The pharmaceutical composition of claim 29, further comprising insulin.

57. A method of treating diabetes in a patient, said method comprising administering an effective amount of a pharmaceutical composition of claim 56 to the patient.

2. (canceled)

3. (canceled)

5. (canceled)

6. (canceled)

10. (canceled)

12. (canceled)

13. (canceled)

15-17. -17. (canceled)

19-28. -28. (canceled)

30-33. -33. (canceled)

35. (canceled)

36. (canceled)

38. (canceled)

40. (canceled)

42-46. -46. (canceled)