Glucagon/GLP-1 receptor co-agonists

• US 8,900,593 B2
• Filed: 01/09/2013
• Issued: 12/02/2014
• Est. Priority Date: 02/15/2007
• Status: Expired due to Fees

• Current Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Original Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Inventors: Day, Jonathan, Patterson, James, Chabenne, Joseph, Smiley, David L., DiMarchi, Richard D., DiMarchi, Maria
• Primary Examiner(s): Li, Ruixiang
• Application Number:
  US13/737,232
• Publication Number:
  US 20130203660A1
• Time in Patent Office: 692 Days
• US Class Current: 424/198.1
• 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: 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
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• 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

Modified glucagon peptides are disclosed having enhanced potency at the glucagon receptor relative to native glucagon. Further modification of the glucagon peptides by forming lactam bridges or the substitution of the terminal carboxylic acid with an amide group produces peptides exhibiting glucagon/GLP-1 receptor co-agonist activity. The solubility and stability of these high potency glucagon analogs can be further improved by modification of the polypeptides by pegylation, substitution of carboxy terminal amino acids, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) and SEQ ID NO: 28 (KRNR).

Claims

1. A glucagon peptide consisting essentially of the amino acid sequence of:

2. The glucagon peptide of claim 1, wherein X3 is Cys-PEG.

3. The glucagon peptide of claim 2, wherein X4 is Thr-CONH2.

4. The glucagon peptide of claim 1, wherein X1 is His and X2 is AIB or X1 is DMIA and X2 is Ser.

5. The glucagon peptide of claim 1, which further comprises a lactam

bridge between amino acids at positions 16 and 20.

6. A pharmaceutical composition comprising the glucagon peptide of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A glucagon peptide consisting essentially of the amino acid sequence of:

8. A pharmaceutical composition comprising the glucagon peptide of claim 7, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.