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

• US 9,125,882 B2
• Filed: 06/28/2012
• Issued: 09/08/2015
• Est. Priority Date: 05/04/2005
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Larsen, Bjarne Due, Petersen, Yvette Miata
• Primary Examiner(s): Bunner, Bridget E
• Application Number:
  US13/536,377
• Publication Number:
  US 20120289466A1
• Time in Patent Office: 1,167 Days
• Field of Search: None
• US Class Current: 1/1
• 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 glucagon-like-peptide-2 (GLP-2) analogue selected from the group consisting of:

2. The GLP-2 analogue of claim 1 selected from the group consisting of:

3. The GLP-2 analogue of claim 1 selected from the group consisting of:

H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH₂(SEQ ID NO;

17),

H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

32),

H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

33),

H-HGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

34),

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

36),

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

37),

H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

38),

H-HGEGTFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

39),

H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

40),

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH₂(SEQ ID NO;

43),

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH₂(SEQ ID NO;

45),

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH₂(SEQ ID NO;

46), and

H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH₂(SEQ ID NO;

47);

or a pharmaceutically acceptable salt thereof.

4. The GLP-2 analogue of claim 1 selected from the group consisting of:

H-HGDGSFSDELSTILDNLAARDFIAWLIQTK-NH₂(SEQ ID NO;

20),

H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH₂(SEQ ID NO;

21),

H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH₂(SEQ ID NO;

25),

H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH₂(SEQ ID NO;

26),

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH₂(SEQ ID NO;

27),

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH₂(SEQ ID NO;

28),

H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH₂(SEQ ID NO;

29), and

H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH₂(SEQ ID NO;

31);

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a GLP-2 analogue of claim 1, or a pharmaceutically acceptable salt thereof, in a mixture with a carrier.

6. The pharmaceutical composition of claim 5, wherein the GLP-2 analogue is a pharmaceutically acceptable acid addition salt.

7. The pharmaceutical composition of claim 5, which is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of said GLP-2 analogue.

8. The GLP-2 analogue of claim 1, wherein the GLP-2 analogue is:

H-HGDGSFSSELSTILDNLAARDFIAWLIQTKKKKKKK-NH₂ (SEQ ID NO;

19)

or a pharmaceutically acceptable salt thereof.

9. The GLP-2 analogue of claim 1, wherein the GLP-2 analogue is:

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH₂ (SEQ ID NO;

45)

or a pharmaceutically acceptable salt thereof.

10. The GLP-2 analogue of claim 1, wherein the GLP-2 analogue is:

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH₂(SEQ ID NO;

37)

or a pharmaceutically acceptable salt thereof.

11. The GLP-2 analogue of claim 1, wherein the GLP-2 analogue is:

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH₂(SEQ ID NO;

27)

or a pharmaceutically acceptable salt thereof.