Glucagon antagonists

• US 6,677,136 B2
• Filed: 05/02/2001
• Issued: 01/13/2004
• Est. Priority Date: 05/03/2000
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Marshall, William S., Stark, Kevin Lee
• Primary Examiner(s): Carlson, Karen Cochrane
• Assistant Examiner(s): Snedden, Sheridan
• Application Number:
  US09/847,249
• Publication Number:
  US 20030032588A1
• Time in Patent Office: 986 Days
• Field of Search: 530/300, 530/387.3, 435/69.7
• US Class Current: 435/69.1
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The present invention concerns therapeutic agents that antagonize the activity of glucagon. In accordance with the present invention, the compounds of the invention comprise:

a. a glucagon antagonist domain, preferably the amino acid sequence of SEQ ID NO: 7, or sequences derived therefrom by phage display, RNA-peptide screening, or the other techniques; and

b. a vehicle, such as a polymer (e.g., PEG or dextran) or an Fc domain, which is preferred;

wherein the vehicle is covalently attached to the glucagon antagonist domain. The vehicle and the glucagon antagonist domain may be linked through the N- or C-terminus of the glucagon antagonist domain. The preferred vehicle is an Fc domain, and the preferred Fc domain is an IgG Fc domain.

Claims

1. A composition of matter of the formula

2. The composition of matter of claim 1 of the formulae

3. The composition of matter of claim 1 of the formula

4. The composition of matter of claim 1, wherein F¹ is an Fc domain.

5. The composition of matter of claim 1 wherein F¹ is an IgG Fc domain.

6. The composition of matter of claim 1 wherein F¹ is an IgG1 Fc domain.

7. The composition of matter of claim 1 wherein F¹ comprises the sequence of SEQ ID NO:

2.

8. The composition of matter of claim 1 wherein the glucagon antagonist domain sequence comprises the formula

9. The composition of matter of claim 8, wherein F¹ is an Fc domain.

10. The composition of matter of claim 8, wherein F¹ is an IgG Fc domain.

11. The composition of matter of claim 10, wherein F¹ is an IgG1 Fc domain.

12. The composition of matter of claim 8, wherein:

X¹ is absent or is H, D or S;

X² is A, C, H, P, S, or T;

X³ is L, M, or Q;

X⁴ is A, D, G, or S;

X⁵ is S or T;

X⁷ is I or T;

X⁸ is E or S;

X⁹ is A, D, E, L, M, or N;

X¹¹ is A or S;

X¹² is K or R;

X¹³ is A, F, or Y;

X¹⁴ is A, L, or N;

X¹⁶ is A, Q, or S;

X²¹ is D, E, L, or M;

X²⁹ is A, E, S, or T.

13. The composition of matter of claim 1, wherein the glucagon antagonist sequence is selected from Table 1 (SEQ ID NOS:

9 to

     72).

14. The composition of matter of claim 8, wherein the glucagon antagonist sequence is selected from Table 1 (SEQ ID NOS:

9 to

     72).

15. The compound of claim 4, wherein the C-terminus is amidated.