Glucagon analogs exhibiting GIP receptor activity

• US 9,249,206 B2
• Filed: 12/27/2012
• Issued: 02/02/2016
• Est. Priority Date: 12/22/2010
• 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., Ward, Brian P.
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US13/728,110
• Publication Number:
  US 20130116173A1
• Time in Patent Office: 1,132 Days
• Field of Search: None
• US Class Current: 1/1
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• 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: C07K 14/605 Glucagons

Abstract

Provided herein are glucagon analogs which exhibit potent activity at the GIP receptor, and, as such are contemplated for use in treating diabetes and obesity. In exemplary embodiments, the glucagon analog of the present disclosures exhibit an EC50 at the GIP receptor which is within the nanomolar or picomolar range.

Claims

1. A peptide comprising

(a) the sequence of SEQ ID NO:

89;

or

(b) SEQ ID NO;

89 with up to 3 amino acid modifications relative to SEQ ID NO;

89 wherein the peptide exhibits agonist activity at each of the human GIP receptor, the human GLP-1 receptor and the human glucagon receptor.

2. A peptide of claim 1, wherein the peptide has less than 100-fold selectivity for the human GLP-1 receptor versus the GIP receptor.

3. A dimer or multimer comprising two or more peptides of claim 1.

4. A pharmaceutical composition comprising a peptide of claim 1, or a dimer or multimer comprising a peptide of claim 1, a conjugate comprising a peptide of claim 1, or a combination thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

5. A method of reducing weight gain or inducing weight loss in a subject in need thereof, comprising administering to a patient in need thereof a pharmaceutical composition of claim 4 in an amount effective to reduce weight gain or induce weight loss.

6. A method of treating diabetes, comprising administering to a patient in need thereof a pharmaceutical composition of claim 4 in an amount effective to lower blood glucose levels.

7. A conjugate comprising a peptide of claim 1 and a conjugate moiety.

8. A peptide comprising the sequence of SEQ ID NO:

89.

9. A pharmaceutical composition comprising the peptide of claim 8, or a dimer or multimer comprising the peptide of claim 8, a conjugate comprising the peptide of claim 8, or a combination thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

10. A method of reducing weight gain or inducing weight loss in a subject in need thereof, comprising administering to a patient in need thereof a pharmaceutical composition of claim 9 in an amount effective to reduce weight gain or induce weight loss.

11. A method of treating diabetes, comprising administering to a patient in need thereof a pharmaceutical composition of claim 9 in an amount effective to lower blood glucose levels.

12. A conjugate comprising the peptide of claim 8 and a conjugate moiety.

13. A dimer or multimer comprising two or more peptides of claim 8.

14. An analog comprising a parent sequence with a total of up to 3 amino acid modifications relative to the parent sequence, wherein the parent sequence is SEQ ID NO:

89, wherein the amino acid modifications are selected from the group consisting of;

a DPP-IV protective amino acid at position 2;

other than AIB, optionally D-Ser;

b. a large, aliphatic, nonpolar amino acid at position 12, optionally Ile;

c. an amino acid other than Arg at position 17, optionally Gln;

d. a small aliphatic amino acid at position 18, other than Ala;

e. an amino acid other than Asp at position 21, optionally Glu;

f. an amino acid other than Gln at position 24, optionally Asn or Ala;

g. an amino acid other than Leu at position 27;

h. an amino acid other than Asp at position 28, optionally Ala; and

i. an amino acid other than Gly at position 29.

15. The analog of claim 14, wherein the analog has less than 100-fold selectivity for the human GLP-1 receptor versus the GIP receptor.

16. A conjugate comprising a peptide of claim 14 and a conjugate moiety.

17. A dimer or multimer comprising two or more peptides of claim 14.

18. A pharmaceutical composition comprising an analog of claim 14, or a dimer or multimer comprising a peptide of claim 14, a conjugate comprising a peptide of claim 14, or a combination thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.