Pancreatic polypeptide family motifs, polypeptides and methods comprising the same

• US 20060135747A1
• Filed: 12/12/2005
• Published: 06/22/2006
• Est. Priority Date: 02/11/2004
• Status: Active Grant

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Parkes, David G., D'Souza, Lawrence J., Levy, Odile Esther, Pittner, Richard A., Ghosh, Soumitra S., Jodka, Carolyn M., Prickett, Kathryn S., Roth, Jonathan David, Ahn, John S., Adams, Sean H.
• Granted Patent: US 7,723,471 B2
• Time in Patent Office: Days
• US Class Current: 530/324
• 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: A61K 38/1709 from mammals
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695

Abstract

The present invention provides novel Pancreatic Polypeptide Family (“PPF”) polypeptides and methods for their use.

Claims

1. A PPF polypeptide comprising an amino acid sequence of Formula (VI):

5. The PPF polypeptide of claim 1, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

266, 267, 274, 282, 320, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479 and 480.

6. The PPF polypeptide of claim 1, wherein said PPF polypeptide further comprises one or more insertions.

7. The PPF polypeptide of claim 1, wherein said PPF polypeptide further comprises an N-terminal cap.

8. The PPF polypeptide of claim 7, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

282, 320, 437, 441, 444, 445 to 447, 452, 454 to 459, 461 to 464, 466, 468 to 470 and 472 to 480.

9. The PPF polypeptide of claim 1, wherein said polypeptide is linked to one or more water-soluble polymers.

10. The PPF polypeptide of claim 9, wherein said polymer is selected from at least one of the group consisting of polyethylene glycol and a fatty acid molecule, wherein said polymer is linked to the N- or C-terminus of the polypeptide, or the side chain of a lysine or serine amino acid residue within the sequence of the polypeptide.

2. A PPF polypeptide comprising an amino acid sequence of Formula (VII):

11. The PPF polypeptide of claim 2, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

266, 437, 438, 439, 442, 462, 469, 470, 471 and 472.

12. The PPF polypeptide of claim 2, wherein said PPF polypeptide further comprises one or more insertions.

13. The PPF polypeptide of claim 2, wherein said PPF polypeptide further comprises an N-terminal cap.

14. The PPF polypeptide of claim 13, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

437, 462, 469, 470 and 472.

15. The PPF polypeptide of claim 2, wherein said polypeptide is linked to one or more water-soluble polymers.

16. The PPF polypeptide of claim 15, wherein said polymer is selected from at least one of the group consisting of polyethylene glycol and a fatty acid molecule, wherein said polymer is linked to the N- or C-terminus of the polypeptide, or the side chain of a lysine or serine amino acid residue within the sequence of the polypeptide.

3. A PPF polypeptide comprising:

an N-terminal fragment consisting essentially of the first 17 amino acid residues of native human PYY (SEQ ID NO;

     2); and

a C-terminal fragment consisting essentially of amino acid residues 18-36 of native human NPY (SEQ ID NO;

     4), wherein the N-terminal and C-terminal fragments are covalently linked, wherein no more than two amino acid residues at the N-terminus of the PYY fragment may be deleted or absent, and wherein no more than nine amino acid substitutions may be made in each of the N-terminal and C-terminal fragments.

4. A PPF polypeptide from about 34 to about 36 amino acids in length, comprising:

an N-terminal fragment consisting essentially of 17 amino acids exhibiting at least 50% sequence identity to the first 17 amino acids of a native PYY; and

a C-terminal fragment consisting essentially of 19 amino acids exhibiting at least 50% sequence identity to amino acids 18-36 of a native NPY, wherein the N-terminal and C-terminal fragments are covalently linked, and wherein one or two amino acid residues at the N-terminus of the PYY fragment may be deleted or absent.

17. A PPF polypeptide comprising SEQ ID NO:

266.

18. A PPF polypeptide comprising SEQ ID NO:

267.

19. A PPF polypeptide comprising SEQ ID NO:

274.

20. A PPF polypeptide comprising SEQ ID NO:

282.

21. A PPF polypeptide comprising SEQ ID NO:

320.

22. A PPF polypeptide comprising SEQ ID NO:

436.

23. A PPF polypeptide comprising SEQ ID NO:

437.

24. A PPF polypeptide comprising SEQ ID NO:

438.

25. A PPF polypeptide comprising SEQ ID NO:

439.

26. A PPF polypeptide comprising SEQ ID NO:

440.

27. A PPF polypeptide comprising SEQ ID NO:

441.

28. A PPF polypeptide comprising SEQ ID NO:

442.

29. A PPF polypeptide comprising SEQ ID NO:

474.

30. A method for altering body composition of a subject, comprising administering to the subject a PPF polypeptide, wherein the PPF polypeptide alters the fat to lean ratio, thereby altering body composition.

31. The method of claim 30, wherein said PPF polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

266, 267, 274, 282, 320, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479 and 480.

32. The method of claim 30, wherein body fat is reduced and lean body mass is maintained or increased.

33. The method of claim 32, wherein the body fat and lean body mass are measured as percent body fat and percent lean body mass, respectively.

34. The method of claim 30, wherein body composition is measured by a method selected from the group consisting of underwater weighing, air displacement plethysmograph, x-ray, MRI, DEXA scan, CT scans, and adiabatic bomb calorimetry.

35. The method of claim 30, wherein body weight is reduced.

36. The method of claim 30, wherein body weight is maintained or increased.

37. The method of claim 30, wherein the PPF polypeptide is administered peripherally.

38. The method of claim 30, wherein the PPF polypeptide is a PYY, a PYY agonist, or a PYY agonist analog.

39. The method of claim 30, further comprising administering to the subject at least one agent selected from the group consisting of an amylin, amylin agonist or amylin analog agonist, salmon calcitonin, a cholecystokinin (CCK) or CCK agonist, a leptin (OB protein) or leptin agonist, an exendin or exendin analog agonist, a GLP-1, GLP-1 agonist or GLP-1 analog agonist, a CCK or CCK agonist, calcitonin, a calcitonin agonist, a small molecule cannabinoid CB1 receptor antagonist, rimonabant, an 11 beta-hydroxysteroid dehydrogenase-1 inhibitor, sibutramine, and phentermine.

40. The method of claim 30 wherein the subject is overweight or obese.

41. The method of claim 30 further comprising dieting.

42. The method of claim 30 wherein the subject is a mammal.

43. The method of claim 42 wherein the mammal is a human.

44. The method of claim 42 wherein the mammal is selected from a group consisting of a primate, a rat, a mouse, a cat, a dog, a pig, a cow, a steer, a horse, a sheep, and a goat.

45. A method for preferentially lowering plasma triglyceride levels in a subject, comprising administering to the subject an amount of a PPF polypeptide effective to lower plasma triglyceride levels, wherein cholesterol levels are lowered to a lesser extent.

46. The method of claim 45, wherein triglyceride levels are lowered and cholesterol levels are not lowered.

47. The method of claim 45, wherein triglyceride levels are lowered and LDL cholesterol levels are not lowered.

48. The method of claim 45, wherein triglyceride levels are lowered and LDL cholesterol levels are lowered to a lesser extent.

49. The method of claim 45, wherein amylase levels are also lowered.

50. A method for reducing body fat or body fat gain in a subject while maintaining or increasing lean body mass, comprising administering to the subject an amount of a PPF polypeptide effective to reduce body fat or body fat gain while maintaining or increasing lean body mass.

51. A method of reducing central body fat in a subject, comprising administering to the subject an amount of a PPF polypeptide effective to reduce central body fat and preserve or increase lean body mass.

52. A method of increasing fatty acid β

-oxidation while preserving or increasing lean body mass in a subject comprising administering to the subject an amount of a PPF polypeptide effective to increase fatty acid β

-oxidation while preserving or increasing lean body mass.

53. A method of treating nonalcoholic steatohepatitis or lipodystrophy in a subject comprising administering to the subject an amount of a PPF polypeptide effective to treat nonalcoholic steatohepatitis or lipodystrophy.