Glucagon-like-peptide-2 (GLP-2) analogues

• US 20070117752A1
• Filed: 11/09/2006
• Published: 05/24/2007
• Est. Priority Date: 05/04/2005
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Larsen, Bjarne, Petersen, Yvette
• Granted Patent: US 7,745,403 B2
• Time in Patent Office: Days
• US Class Current: 514/11.700
• CPC Class Codes: A61K 35/54 Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• 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 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 39/02 Antidotes
• 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: C12N 2710/10043 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2710/20043 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2710/22043 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2760/20243 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

GLP-2 analogues are disclosed which comprise one of more substitutions as compared to [hGly2]GLP-2 and which improved biological activity in vivo and/or improved chemical stability, e.g., as assessed in in vitro stability assays. More particularly, preferred GLP-2 analogues disclosed herein comprise substitutions at one or more of positions 8, 16, 24 and/or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 (as mentioned in the introduction) and one or more of positions 3, 5, 7, 10 and 11, and/or a deletion of one or more of amino acids 31 to 33 and/or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogues are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy. Also disclosed are methods and kits for selecting a patient from populations suited for treatment with GLP-2 analogues.

Claims

1. A method of selecting a patient for GLP-2 analogue therapy, said method comprising the steps:

(a) determining whether said patient has a stomach or bowel disorder; and

(b) determining whether said patient has or is at increased risk of having abnormal tissue growth, wherein not having or not being at increased risk of having said abnormal tissue growth indicates said patient for GLP-2 analogue therapy.

2. The method of claim 1, further comprising the step:

(c) administering a GLP-2 analogue to said patient.

3. The method of claim 2, wherein said GLP-2 analogue is administered in an amount effective to treat said patient for said stomach or bowel disorder.

4. The method of claim 2, wherein GLP-2 analogue is a GLP-2 analogue of general Formula I.

5. The method of claim 4, wherein said GLP-2 analogue comprises a plurality of substitutions of the amino acid sequence of wild-type GLP-2 (1-33) at positions selected from the group consisting of X3, X7, X16, X24, X28, X31, X32, and X33.

6. The method of claim 5, wherein the GLP-2 analogue comprises at least one substitution selected from the group consisting of X3 is Glu, X7 is Ser, X16 is Ala, X24 is Ala, X28 is Ala, X31 is Ile, X32 is Thr, and X33 is Asp, and a deletion of zero, one, two, or three of the amino acid residues in positions X31, X32, and X33;

or a pharmaceutically acceptable salt or derivative thereof.

7. The method of claim 5, wherein said GLP-2 analogue is selected from the group consisting of:

8. The method of claim 1, wherein said abnormal tissue growth is caused by a neoplasm.

9. The method of claim 8, wherein said neoplasm is selected from the group consisting of gastric mucosal neoplasm, colonic mucosal neoplasm, adenocarcinoma, colon cancer, colorectal cancer, small intestine cancer, and stomach cancer.

10. The method of claim 1, wherein said stomach or bowel disorder is selected from the group consisting of an ulcer, a digestion disorder, a malabsorption syndrome, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, entiritis, regional enteritis (Crohn'"'"'s disease), ulcerative colitis, small intestine damage, and short bowel syndrome.

11. A kit comprising:

(a) a GLP-2 analogue represented by general Formula I; and

(b) instructions for administering said GLP-2 analogue to a patient not having or not at an increase risk of developing abnormal tissue growth.

12. The kit of claim 11, wherein said GLP-2 analogue comprises a plurality of substitutions of the amino acid sequence of wild-type GLP-2 (1-33) at positions selected from the group consisting of X3, X7, X16, X24, X28, X31, X32, and X33.

13. The kid of claim 11, wherein the GLP-2 analogue comprising at least one substitution selected from the group consisting of X3 is Glu, X7 is Ser, X16 is Ala, X24 is Ala, X28 is Ala, X31 is Ile, X32 is Thr, and X33 is Asp, and a deletion of zero, one, two, or three of the amino acid residues in positions X31, X32, and X33;

or a pharmaceutically acceptable salt or derivative thereof.

14. The kid of claim 11, wherein said GLP-2 analogue is selected from the group consisting of:

15. The kid of claim 11, wherein said GLP-2 analogue is provided in a pharmaceutically acceptable carrier.

16. The kid of claim 11, wherein said abnormal tissue growth is caused by a neoplasm.

17. The kid of claim 11, wherein said instructions further indicate that said GLP-2 analogue is to be administered for the treatment of a stomach or bowel disorder.

18. The kid of claim 11, wherein said instructions further indicate that said GLP-2 analogue is to be administered for the treatment of any condition selected from the group consisting of an ulcer, a digestion disorder, a malabsorption syndrome, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn'"'"'s disease), ulcerative colitis, small intestine damage, and short bowel syndrome.