IP Library › Granted Patent US 9,125,882
Granted Patent B2
US 9,125,882 · App. 13/536,377 · Granted Sep 8, 2015

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

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Quick Facts
Patent No.
US 9,125,882
App. No.
13/536,377
Granted
Sep 8, 2015
Kind
B2
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 (205)

1. A glucagon-like-peptide-2 (GLP-2) analogue selected from the group consisting of:

(SEQ ID NO: 1)

H-HGEGTFSDELATILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1809),

(SEQ ID NO: 2)

H-HGEGTFSDELATILDALAARIFIAWLIATKKKKKKK-NH 2

(Compound 1810),

(SEQ ID NO: 3)

H-HGDGSPSDELATILDALAARDFIAWLIATKITD-NH 2

(Compound 1811),

(SEQ ID NO: 4)

H-HGEGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2

(Compound 1812),

(SEQ ID NO: 5)

H-HGDGSFSDELATILDALAARDFIAWLIATKITD-NH 2

(Compound 1813),

(SEQ ID NO: 6)

H-HGDGSFSDELATILDNLAARDFIAWLIATKITD-NH 2

(Compound 1814),

(SEQ ID NO: 7)

H-HGEGSFSDELATILDALAARDFIAWLIATKITD-NH 2

(Compound 1815),

(SEQ ID NO: 8)

H-HGDGSFSSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1818),

(SEQ ID NO: 9)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1819),

(SEQ ID NO: 10)

H-HGDGSFTSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1820),

(SEQ ID NO: 11)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1821),

(SEQ ID NO: 12)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1822),

(SEQ ID NO: 13)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1823),

(SEQ ID NO: 14)

H-HGDGSFIDELATILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1824),

(SEQ ID NO: 15)

H-HGDGSFSSELATILDNLAARDFIAWLIQTK-NH 2

(Compound 1825),

(SEQ ID NO: 17)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1827),

(SEQ ID NO: 18)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1828),

(SEQ ID NO: 19)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2

(Compound 1829),

(SEQ ID NO: 20)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTK-NH 2

(Compound 1830),

(SEQ ID NO: 21)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH 2

(Compound 1831),

(SEQ ID NO: 22)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTK-NH 2

(Compound 1832),

(SEQ ID NO: 23)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTK-NH 2

(Compound 1833),

(SEQ ID NO: 24)

H-HGDGSFTSELATILDNLAARDFIAWLIQTK-NH 2

(Compound 1834),

(SEQ ID NO: 25)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH 2

(Compound 1835),

(SEQ ID NO: 26)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH 2

(Compound 1836),

(SEQ ID NO: 27)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH 2

(Compound 1839),

(SEQ ID NO: 28)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2

(Compound 1840),

(SEQ ID NO: 29)

H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH 2

(Compound 1841),

(SEQ ID NO: 30)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTK-NH 2

(Compound 1842),

(SEQ ID NO: 31)

H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH 2

(Compound 1843),

(SEQ ID NO: 32)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1844),

(SEQ ID NO: 33)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1845),

(SEQ ID NO: 34)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1846),

(SEQ ID NO: 35)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1847),

(SEQ ID NO: 36)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1848),

(SEQ ID NO: 37)

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1849),

(SEQ ID NO: 38)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1850),

(SEQ ID NO: 39)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1851),

(SEQ ID NO: 40)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2

(Compound 1852),

(SEQ ID NO: 41)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITD-NH 2

(Compound 1853),

(SEQ ID NO: 42)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITD-NH 2

(Compound 1854)

(SEQ ID NO: 43)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2

(Compound 1855),

(SEQ ID NO: 44)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITD-NH 2

(Compound 1856),

(SEQ ID NO: 45)

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2

(Compound 1857),

(SEQ ID NO: 46)

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2

(Compound 1858),

(SEQ ID NO: 47)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH 2

(Compound 1859),

(SEQ ID NO: 48)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITD-NH 2

(Compound 1860), and

(SEQ ID NO: 49)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITD-NH 2

(Compound 1861),

or a pharmaceutically acceptable salt thereof.

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

(SEQ ID NO: 24)

H-HGDGSFTSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 34)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITDK 6 NH 2 ,

(SEQ ID NO: 35)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITDK 6 -NH 2 ,

(SEQ ID NO: 36)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDK 6 -NH 2 ,

(SEQ ID NO: 37)

H-HGEGSFSSELATILDALAARDFIAWLIATKITDK 6 -NH 2 ,

(SEQ ID NO: 43)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 45)

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2 , 

and

(SEQ ID NO: 46)

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2 .

or a pharmaceutically acceptable salt thereof.

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

H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 (SEQ ID NO:17),

H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO:32),

H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO:33),

H-HGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO:34),

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO:36),

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO:37),

H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO:38),

H-HGEGTFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO:39),

H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 (SEQ ID NO:40),

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2 (SEQ ID NO:43),

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2 (SEQ ID NO:45),

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2 (SEQ ID NO:46), and

H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH 2 (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-NH 2 (SEQ ID NO:20),

H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH 2 (SEQ ID NO:21),

H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH 2 (SEQ ID NO:25),

H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH 2 (SEQ ID NO:26),

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH 2 (SEQ ID NO:27),

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 (SEQ ID NO:28),

H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH 2 (SEQ ID NO:29), and

H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH 2 (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-NH 2 (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-NH 2 (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-NH 2 (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-NH 2 (SEQ ID NO:27)

or a pharmaceutically acceptable salt thereof.

Assignments (4)
RELEASE OF SECURITY INTEREST Recorded May 17, 2023
From: ZOOLANDER SA LLC
To: ZEALAND PHARMA A/S
Reel/Frame 063672/0342 →
RELEASE OF SECURITY INTEREST Recorded May 11, 2023
From: ZOOLANDER SA LLC
To: ZEALAND PHARMA A/S
Reel/Frame 063624/0547 →
PATENT SECURITY AGREEMENT Recorded Dec 27, 2021
From: ZEALAND PHARMA A/S
To: ZOOLANDER SA LLC
Reel/Frame 058593/0261 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 13, 2014
From: LARSEN, BJARNE DUE; PETERSEN, YVETTE MIATA
To: ZEALAND PHARMA A/S
Reel/Frame 033102/0693 →