PEGYLATED OXM VARIANTS

• US 20150258208A1
• Filed: 05/29/2015
• Published: 09/17/2015
• Est. Priority Date: 06/02/2011
• Status: Active Grant

• Current Assignee: Opko Biologics Ltd. (Opko Health, Inc.)
• Original Assignee: Opko Biologics Ltd. (Opko Health, Inc.)
• Inventors: FIMA, Udi, HERSHKOVITZ, Oren
• Granted Patent: US 10,166,295 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Abstract

A composition which includes oxyntomodulin and polyethylene glycol polymer (PEG polymer) linked via a reversible linker such as 9-fluorenylmethoxycarbonyl (Fmoc) or sulfo-9-fluorenylmethoxycarbonyl (FMS) is disclosed. Pharmaceutical compositions comprising the reverse pegylated oxyntomodulin and methods of using same are also disclosed.

Claims

1. A composition consisting of an oxyntomodulin, a polyethylene glycol polymer (PEG polymer) and 9-fluorenylmethoxycarbonyl (Fmoc) or sulfo-9-fluorenylmethoxycarbonyl (FMS), wherein said PEG polymer is attached to the amino terminus of said oxyntomodulin via Fmoc or FMS.

2. The composition of claim 1, wherein said PEG polymer is a PEG polymer with a sulfhydryl moiety.

3. The composition of claim 2, wherein said PEG polymer is PEG30.

4. A pharmaceutical composition comprising the composition of claim 3, and a pharmaceutical acceptable carrier.

5. The composition of claim 1, wherein said oxyntomodulin consists of the amino acid sequence set forth in SEQ ID NO:

1.

11. A method of improving the area under the curve (AUC) of oxyntomodulin, comprising administering to a subject the composition of claim 4.

13. A method of reducing the dosing frequency of oxyntomodulin, comprising administering to a subject the composition of claim 4.

15. A method for extending the biological half-life of oxyntomodulin, comprising administering to a subject the composition of claim 4.

16. The method of claim 15, wherein said oxyntomodulin is released into a biological fluid by chemically hydrolyzing FMS or Fmoc linker from said composition.

17. The method of claim 16, wherein the released oxyntomodulin is intact and regains GLP-1 and glucagon receptor binding activity.

18. The method of claim 17, wherein said biological fluid is blood, sera, or cerebrospinal fluid.

23. A method of inducing glucose tolerance in a subject in need thereof comprising administering to a subject the composition of claim 4.

25. A method of inducing glycemic control in a subject in need thereof comprising administering to a subject the composition of claim 4.

27. A method of reducing food intake in a subject thereof comprising administering to a subject the composition of claim 4.

29. A method of reducing body weight in a subject comprising administering to a subject the composition of claim 4.

31. A method of improving the cholesterol levels in a subject comprising administering to a subject the composition of claim 4.

33. A method of increasing insulin sensitivity in a subject comprising administering to a subject the composition of claim 4.

35. A method of reducing insulin resistance in a subject comprising administering to a subject the composition of claim 4.

37. A method of increasing energy expenditure in a subject comprising administering to a subject the composition of claim 4.

6. A composition consisting of an oxyntomodulin, a polyethylene glycol polymer (PEG polymer) and 9-fluorenylmethoxycarbonyl (Fmoc) or sulfo-9-fluorenylmethoxycarbonyl (FMS), wherein said PEG polymer is attached to a lysine residue on position number twelve (Lys12), or to a lysine residue on position number thirty (Lys30), of said oxyntomodulin'"'"'s amino acid sequence via Fmoc or FMS.

7. The composition of claim 6, wherein said PEG polymer is a PEG polymer with a sulfhydryl moiety.

8. The composition of claim 7, wherein said PEG polymer is PEG30.

9. A pharmaceutical composition comprising the composition of claim 8 and a pharmaceutical acceptable carrier.

10. The composition of claim 6, wherein said oxyntomodulin consists of the amino acid sequence set forth in SEQ ID NO:

1.

12. A method of improving the area under the curve (AUC) of oxyntomodulin comprising administering to a subject the composition of claim 9.

14. A method of reducing the dosing frequency of oxyntomodulin, comprising administering to a subject the composition of claim 9.

19. A method for extending the biological half-life of oxyntomodulin, comprising administering to a subject the composition of claim 9.

20. The method of claim 19, wherein said oxyntomodulin is released into a biological fluid by chemically hydrolyzing FMS or Fmoc linker from said composition.

21. The method of claim 20, wherein the released oxyntomodulin is intact and regains GLP-1 and glucagon receptor binding activity.

22. The method of claim 21, wherein said biological fluid is blood, sera, or cerebrospinal fluid.

24. A method of inducing glucose tolerance in a subject in need thereof comprising administering to a subject the composition of claim 9.

26. A method of inducing glycemic control in a subject in need thereof comprising administering to a subject the composition of claim 9.

28. A method of reducing food intake in a subject thereof comprising administering to a subject the composition of claim 9.

30. A method of reducing body weight in a subject comprising administering to a subject the composition of claim 9.

32. A method of improving the cholesterol levels in a subject comprising administering to a subject the composition of claim 9.

34. A method of increasing insulin sensitivity in a subject comprising administering to a subject the composition of claim 9.

36. A method of reducing insulin resistance in a subject comprising administering to a subject the composition of claim 9.

38. A method of increasing energy expenditure in a subject comprising administering to a subject the composition of claim 9.