US2017137487A1PendingUtilityA1
Glucagon-like-peptide-2 (glp-2) analogues
Est. expiryMay 4, 2025(expired)· nominal 20-yr term from priority
A61P 39/00A61P 5/00A61P 3/04A61P 43/00A61P 39/02A61P 3/00A61P 35/00A61P 31/04A61P 29/00A61P 1/14A61P 1/04A61P 1/00A61P 1/12A61P 19/10A61K 47/26C12N 2710/20043A61K 38/00C07K 14/605A61K 9/0019A61K 48/00C12N 2760/20243A61K 35/54A61K 9/19C12N 7/00A61K 35/74C12N 2710/10043A61K 38/26C12N 2710/22043
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Claims
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
exact text as granted — not AI-modified1 . A glucagon-like peptide 2 (GLP-2) analogue represented by general Formula I:
R 1 —Z 1 -His-X2-X3-Gly-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-Ala-X19-X20-X21-Phe-Ile-X24-Trp-Leu-lie-X28-Thr-Lys-X31-X32-X33-Z 2 —R 2
wherein: R 1 is hydrogen, C 1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl X2 is Gly, Ala or Sar X3 is Glu or Asp X5 is Ser or Thr X6 is Phe or Pro X7 is Ser or Thr X8 is Asp or Ser X9 is Glu or Asp X10 is Met, Leu, Nle or an oxidatively stable Met-replacement amino acid X11 is Asn, Ala, Lys or Ser X12 is Thr or Lys X13 is Ile, Glu or Gln X14 is Leu, Met or Nle X15 is Asp or Glu X16 is Asn or Ala X17 is Leu or Glu X18 is Ala or Aib X19 is Ala or Thr X20 is Arg or Lys X21 is Asp or Ile X24 is Asn, Ala or Glu X28 is Gln, Ala or Asn X31 is Pro, Ile or deleted X32 is Thr or deleted X33 is Asp, Asn or deleted R 2 is NH 2 or OH; Z 1 and Z 2 are independently absent or a peptide sequence of 3-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Met and Orn; and wherein the GLP-2 analogue comprises one or more of substitutions selected from X8 is Ser and/or X16 is Ala and/or X24 is Ala and/or X28 is Ala; or a pharmaceutically acceptable salt or derivative thereof.
2 . The GLP-2 analogue of claim 1 which is represented by general Formula II:
R 1 —Z 1 -His-Gly-X3-Gly-X5-Phe-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-Ala-X19-Arg-Asp-Phe-Ile-X24-Trp-Leu-Ile-X28-Thr-Lys-X31-X32-X33-Z 2 —R 2
wherein:
R 1 is hydrogen, C 1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl
X3 is Glu or Asp
X5 is Ser or Thr
X7 is Ser or Thr
X8 is Asp or Ser
X9 is Glu or Asp
X10 is Met, Leu, Nle or an oxidatively stable Met-replacement amino acid
X11 is Asn, Ala, Lys or Ser
X12 is Thr or Lys
X13 is Ile, Glu or Gln
X14 is Leu, Met or Nle
X15 is Asp or Glu
X16 is Asn or Ala
X17 is Leu or Glu
X19 is Ala or Thr
X24 is Asn or Ala
X28 is Gln, Ala or Asn
X31 is Pro, Ile or deleted
X32 is Thr or deleted
X33 is Asp or deleted
R 2 is NH 2 or OH;
Z 1 and Z 2 are independently absent or a peptide sequence of 3-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Met and Orn; and
wherein the GLP-2 analogue comprises one or more of substitutions selected from
X8 is Ser and/or X16 is Ala and/or X24 is Ala and/or X28 is Ala;
or a pharmaceutically acceptable salt or derivative thereof.
3 . The GLP-2 analogue of claim 1 or claim 2 which is represented by general Formula III:
R 1 —Z 1 -His-Gly-X3-Gly-X5-Phe-X7-X8-Glu-X10-X11-Thr-Ile-Leu-Asp-X16-Leu-Ala-Ala-Arg-Asp-Phe-Ile-X24-Trp-Leu-Ile-X28-Thr-Lys-X31-X32-X33-Z 2 —R 2
wherein:
R 1 is hydrogen, C 1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl
X3 is Glu or Asp
X5 is Ser or Thr
X7 is Ser or Thr
X8 is Asp or Ser
X10 is Met, Leu, Nle, or an oxidatively stable Met-replacement amino acid
X11 is Asn, Ala, Lys or Ser
X24 is Asn or Ala
X28 is Gln or Ala
X31 is Pro or deleted
X32 is Thr or deleted
X33 is Asp or deleted
R 2 is NH 2 or OH;
Z 1 and Z 2 are independently absent or a peptide sequence of 3-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Met and Orn; and
wherein the GLP-2 analogue comprises one or more of substitutions selected from
X8 is Ser and/or X16 is Ala and/or X24 is Ala and/or X28 is Ala;
or a pharmaceutically acceptable salt or derivative thereof.
4 . The GLP-2 analogue of any one of claims 1 to 3 , wherein the GLP-2 analogue has at least 60% amino acid sequence identity to wild-type GLP-2 (1-33) and has the biological activity of causing an increase in intestinal mass in vivo.
5 . The GLP-2 analogue of any one of the preceding claims, wherein the GLP-2 analogue comprises more than one of the substitutions at positions X8, X16, X24 and/or X28 and/or one of more of said substitutions in combination with one or more substitutions at positions X3, X5, X7, X10 and/or X11.
6 . The GLP-2 analogue of claim 5 , wherein said substitutions at position X10 is Leu, Nle, or an oxidatively stable Met-replacement amino acid, such as Met(O) or Met(O) 2 .
7 . The GLP-2 analogue of claim 5 , wherein said substitutions at position X11 is Ala, Ser, or Lys.
8 . The GLP-2 analogue of claim 4 , wherein the GLP-2 analogue comprises one or more of the following groups of substitutions:
Ser8, Ala16 Ser8, Ala24 Ser8, Ala28 Ala16, Ala24 Ala16, Ala28 Ala24, Ala28 Ser8, Ala16, Ala24 Ser8, Ala16, Ala28 Ser8, Ala24, Ala28 Ala16, Ala24, Ala28 Ser8, Ala16, Ala24, Ala28
9 . The GLP-2 analogue of claim 5 , wherein the GLP-2 analogue comprises one or more of the following groups of substitutions:
Glu3, Leu10, Ala11,24 Glu3, Thr5, Leu10, Ser11, Ala16,24,28 Glu3, Thr5, Leu10, Lys11, Ala16,24,28 Glu3, Thr5, Ser8, Leu10, Lys11, Ala16,24,28 Glu3, Thr5, Ser8,11, Leu10, Ala16,24,28 Glu3, Thr5, Ser8,11, Leu10, Ala16,24,28 Glu3, Ser8,11, Leu10, Ala16,24,28 Glu3, Leu10, Ser11, Ala16,24,28 Glu3, Leu10, Lys11, Ala16,24,28 Glu3, Thr5, Leu10, Ala11,16,24,28 Glu3, Thr5, Leu10, Ala11,16,24,28, Ile21 Glu3, Thr5, Ser8, Leu10, Ala11,16,24,28 Glu3, Ser8, Leu10, Ala11,16,24,28 Glu3, Leu10, Ala11,16,24,28 Thr7, Leu10, Ala11, 24 Thr7, Leu10, Lys11, Ala24 Thr7, Leu10, Ser11, Ala24 Thr7, Leu10, Ser8,11, Ala24 Thr7, Ser8, Leu10, Ala11,24 Thr7, Ser8, Leu10, Lys11, Ala24 Ser8, Leu10, Ala11,24 Leu10, Ala24 Leu10, Ala11, Ala24 Leu10, Ala11,24,28 Leu10, Ala11,16,24,28 Leu10, Lys11, Ala24 Leu10, Ser11, Ala24 Leu10, Ser8,11, Ala24; or a deletion at one or more of positions X31-X33.
10 . The GLP-2 analogue of any of the preceding claims which is disclosed in Table 1 herein or a pharmaceutically acceptable salt or derivative thereof.
11 . The GLP-2 analogue of claim 10 which is:
1834
H-HGDGSFTSELATILDNLAARDFIAWLIQTK-NH 2
1846
H-HGEGSFSSELSTILDALAARDFIAWLIATKITDK 6 NH 2
1847
H-HGEGSFSDELSTILDALAARDFIAWLIATKITDK 6 -NH 2
1848
H-HGEGTFSSELATILDALAARDFIAWLIATKITDK 6 -NH 2
1849
H-HGEGSFSSELATILDALAARDFIAWLIATKITDK 6 -NH 2
1855
H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2
1857
H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2
1858
H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2
12 . The GLP-2 analogue of any one of claims 1 to 9 , wherein the GLP-2 analogue comprises more than one of the substitutions at positions X3, X7, X16, X24, X28, X31, X32 and/or X33.
13 . The GLP-2 analogue of claim 12 , wherein the GLP-2 analogue comprises one or more of substitutions selected from 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 the amino acid residues in positions X31, X32 and X33 are optionally deleted; or a pharmaceutically acceptable salt or derivative thereof.
14 . The GLP-2 analogue of claim 12 or claim 13 which is:
1827
H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH2
1844
H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH2
1845
H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH2
1846
H-HGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH2
1848
H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2
1849
H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2
1850
H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH2
1851
H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH2
1852
H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH2
1855
H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH2
1857
H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH2
1858
H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH2
1859
H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH2;
or a pharmaceutically acceptable salt or derivative thereof.
15 . The GLP-2 analogue of any one of claims 1 to 9 , wherein the GLP-2 analogue comprises more than one of the substitutions at positions X3, X8 and/or X24.
16 . The GLP-2 analogue of claim 15 , wherein the GLP-2 analogue comprises one or more of substitutions selected from X3 is Asp, X8 is Asp and X24 is Ala; and the amino acid residues in positions X31, X32 and X33 are optionally deleted; or a pharmaceutically acceptable salt or derivative thereof.
17 . The GLP-2 analogue of claim 15 or claim 16 which is:
1830
H-HGDGSFSDELSTILDNLAARDFIAWLIQTK-NH2
1831
H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH2
1835
H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH2
1836
H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH2
1839
H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH2
1840
H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH2
1841
H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH2
1843
H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH2;
or a pharmaceutically acceptable salt or derivative thereof.
18 . The GLP-2 analogue of any one of claims 1 to 9 which possesses a substitution at one or more of positions X3, X33, X10, X11, X16 and/or X24.
19 . A GLP-2 analogue of any one of the preceding claims for use in therapy.
20 . A pharmaceutical composition comprising a GLP-2 analogue of any one of the preceding claims, or a salt or derivative thereof, in admixture with a carrier.
21 . The pharmaceutical composition of claim 20 , wherein the GLP-2 analogue is a pharmaceutically acceptable acid addition salt.
22 . The pharmaceutical composition of claim 20 or claim 21 , 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.
23 . Use of a GLP-2 analogue of any one of claims 1 to 18 for the preparation of a medicament for the treatment and/or prevention of a stomach and bowel-related disorder.
24 . The use of claim 23 , wherein the stomach and bowel-related disorder is ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (for example arising from gluten induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestine damage or short bowel syndrome.
25 . The use of claim 23 , wherein the stomach and bowel-related disorder is radiation enteritis, infectious or post-infectious enteritis, or small intestinal damage due to toxic or other chemotherapeutic agents.
26 . Use of a GLP-2 analogue of any one of claims 1 to 18 for the preparation of a medicament for the treatment and/or prevention of a side effect of chemotherapy or radiation treatment.
27 . The use of claim 26 , wherein the side effect of chemotherapy is diarrhoea, abdominal cramping, vomiting or structural and functional damage of the intestinal epithelium resulting from chemotherapy treatment.
28 . Use of a GLP-2 analogue of any one of claims 1 to 18 for the preparation of a medicament for the treatment of neo-natals, osteoporosis or DPP-IV (dipeptidylpeptidase-IV) mediated conditions.
29 . Use of a GLP-2 analogue of any one of claims 1 to 18 for the preparation of a medicament for the treatment and/or prevention of a condition involving malnutrition.
30 . The use of claim 29 , wherein the condition involving malnutrition is cachexia or anorexia.
31 . A nucleic acid molecule comprising a nucleic acid sequence encoding a GLP-2 analogue of any one of claims 1 to 18 .
32 . An expression vector comprising the nucleic acid sequence of claim 31 , in combination with control sequences to directed its expression.
33 . A host cell transformed the expression vector of claim 32 .
34 . A method of producing the GLP-2 analogue of any one of claims 1 to 18 , the method comprising culturing the host cells of claim 22 under conditions suitable for expressing the GLP-2 analogue and purifying the GLP-2 analogue thus produced.
35 . A nucleic acid molecule according to claim 31 , an expression vector according to claim 32 , or a host cell according to claim 33 , for use in therapy.
36 . Use of a nucleic acid molecule according to claim 31 , an expression vector according to claim 32 , or a host cell according to claim 33 , in the preparation of a medicament for the treatment and/or prevention of a stomach and bowel-related disorder, or for the treatment and/or prevention of a side effect of chemotherapy or radiation treatment, or for the treatment of neo-natals, osteoporosis or DPP-IV (dipeptidylpeptidase-IV) mediated conditions.
37 . A method of treating a stomach and bowel-related disorder in a patient in need thereof by administering an effective amount a GLP-2 analogue of any one of claims 1 to 17 , a nucleic acid molecule according to claim 31 , an expression vector according to claim 32 , or a host cell according to claim 33 .
38 . The method of claim 37 , wherein the stomach and bowel-related disorder is ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (for example arising from gluten induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestine damage or short bowel syndrome.
39 . The method of claim 37 , wherein the stomach and bowel-related disorder is radiation enteritis, infectious or post-infectious enteritis, or small intestinal damage due to toxic or other chemotherapeutic agents.
40 . A method of treating or preventing a side effect of chemotherapy or radiation therapy to a patient in need thereof, the method comprising administering an effective amount a GLP-2 analogue of any one of claims 1 to 18 , a nucleic acid molecule according to claim 31 , an expression vector according to claim 32 , or a host cell according to claim 33 .
41 . The method of claim 40 , wherein the side effect of chemotherapy is diarrhoea, abdominal cramping, vomiting or structural or functional damage of the intestinal epithelium resulting from chemotherapy treatment.
42 . A method of treating neo-natal disorders, obesity, osteoporosis or DPP-IV (dipeptidylpeptidase-IV) mediated conditions in a patient in need thereof, the method comprising administering an effective amount a GLP-2 analogue of any one of claims 1 to 18 , a nucleic acid molecule according to claim 31 , an expression vector according to claim 32 , or a host cell according to claim 33 .
43 . A therapeutic kit comprising a cancer chemotherapy drug and a GLP-2 analogue according to any one of claims 1 to 18 , a nucleic acid molecule according to claim 31 , an expression vector according to claim 32 , or a host cell according to claim 33 , each optionally in combination with a pharmaceutically acceptable carrier.
44 . A pharmaceutical composition comprising a cancer chemotherapy drug and a GLP-2 analogue according to any one of claims 1 to 18 , a nucleic acid molecule according to claim 31 , an expression vector according to claim 32 , or a host cell according to claim 33 in combination with a pharmaceutically acceptable carrier.
45 . A GLP-2 analogue of any of claims 1 to 17 wherein said analog has enhanced stability relative to Gly2-GLP-2.
46 . A GLP-2 analogue of any of claims 1 to 17 which is further characterized in having an observed purity of at least 70% relative to the initial purity in conditions selected from the group consisting of 0.1 M HCl after 12 days, 0.5% H 2 O 2 after 3 days, and 0.1 M NH 4 HCO 3 after 6 days
47 . A GLP-2 analogue of any of claims 1 to 17 which is further characterized in having an observed purity of at least 60% relative to initial purity in a solution of HCl 0.1 M after 12 days.
48 . A GLP-2 analogue of any of claims 1 to 17 which is further characterized in having an observed purity of at least 70% relative to initial purity in a solution of NH 4 HCO 3 0.1 M after 6 days.Join the waitlist — get patent alerts
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