Exendins and Exendin Agonists Modified with Albumin

• US 20080214467A1
• Filed: 04/11/2008
• Published: 09/04/2008
• Est. Priority Date: 04/30/1999
• Status: Active Grant

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., PRICKETT, Kathryn S.
• Granted Patent: US 7,608,692 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• 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 3/08 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

Abstract

Novel modified exendins and exendin agonists having an exendin or exendin agonist linked to one or more molecular weight increasing compounds, for example, albumin, polyethylene glycol polymers, and related formulations and dosages and methods of administration thereof are provided. These modified exendins and exendin agonists, compositions and methods are useful in treating diabetes and conditions that would be benefited by lowering plasma glucose or delaying and/or slowing gastric emptying or inhibiting food intake.

Claims

1. A pharmaceutical composition comprising (A) a compound which comprises exendin-4 linked to albumin through an epsilon amino group on a C-terminal lysine amino acid on the exendin-4;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2; and

(B) a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 1, wherein the C-terminal amino acid is lysine.

19. A kit comprising the pharmaceutical composition of claim 1 and instructions for use.

2. A pharmaceutical composition comprising (A) a compound which comprises exendin-4 linked to albumin through a C-terminal amino acid on the exendin-4;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2; and

(B) a pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 2, wherein the exendin-4 is linked to the albumin through an epsilon amino group on the C-terminal lysine amino acid on the exendin-4.

5. A kit comprising the pharmaceutical composition of claim 2 and instructions for use.

6. A pharmaceutical composition comprising (A) a compound which comprises exendin-4 linked to albumin through (i) a C-terminal lysine amino acid on the exendin-4 or (ii) an internal lysine amino acid on the exendin-4;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2; and

(B) a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, wherein the exendin-4 is linked to the albumin through the C-terminal lysine amino acid on the exendin-4.

8. The pharmaceutical composition of claim 7, wherein the exendin-4 is linked to the albumin through an epsilon amino group on the C-terminal lysine amino acid on the exendin-4.

9. The pharmaceutical composition of claim 6, wherein the exendin-4 is linked to the albumin through the internal lysine amino acid on the exendin-4.

10. The pharmaceutical composition of claim 9, wherein the exendin-4 is linked to the albumin through an epsilon amino group on the internal lysine amino acid on the exendin-4.

11. A pharmaceutical composition comprising (A) a compound which comprises exendin-4 linked to albumin through (i) a C-terminal amino acid on the exendin-4, (ii) an internal lysine amino acid on the exendin-4, (iii) an internal aspartic acid amino acid on the exendin-4, (iv) an internal glutamic acid amino acid on the exendin-4, (v) an internal cysteine amino acid on the exendin-4, or (vi) an N-terminal amino acid on the exendin-4;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2; and

(B) a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, wherein the exendin-4 is linked to albumin through the C-terminal amino acid on the exendin-4.

13. The pharmaceutical composition of claim 11, wherein the exendin-4 is linked to albumin through the internal lysine amino acid on the exendin-4.

14. The pharmaceutical composition of claim 11, wherein the exendin-4 is linked to albumin through the internal aspartic acid amino acid on the exendin-4.

15. The pharmaceutical composition of claim 11, wherein the exendin-4 is linked to albumin through the internal glutamic acid amino acid on the exendin-4.

16. The pharmaceutical composition of claim 11, wherein the exendin-4 is linked to albumin through the internal cysteine amino acid on the exendin-4.

17. The pharmaceutical composition of claim 11, wherein the exendin-4 is linked to albumin through the N-terminal amino acid on the exendin-4.

18. A kit comprising the pharmaceutical composition of claim 11 and instructions for use.

20. A pegylated peptide selected from the group consisting of SEQ ID NO:

230, 231, 233, 234, 235, 236, 237, 238, 239, and 240.