GLUCAGON-LIKE-PEPTIDE-2 (GLP-2) ANALOGUES
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.
1 - 48 . (canceled)
49 . A method for treating anorexia in a patient in need thereof comprising administering to the patient a pharmaceutical composition formulated for parenteral administration comprising:
(a) the glucagon-like peptide 2 (GLP-2) analogue [Gly2, Glu3, Leu10, Ala11, 24]hGLP-2-NH 2 represented by the sequence:
(SEQ ID NO: 4)
HGEGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,
or a pharmaceutically acceptable salt or derivative thereof,
(b) a pharmaceutically acceptable carrier comprising an aqueous carrier and the gelling agent hyaluronic acid; and
(c) a solubility enhancer selected from Tween 20, Tween 80, Poloxamers, e.g., Pluronic F-68, Pluronic F-127, Brij 35, Brij 72, or cremophor EL,
wherein the glucagon-like peptide 2 (GLP-2) analogue is administered in an amount sufficient to treat said anorexia.
50 . The method of claim 49 , wherein the pharmaceutically acceptable carrier further comprises a histidine buffer.
51 . A method of producing the GLP-2 analogue [Gly2, Thr7, Leu10, Lys11, Ala24]hGLP-2(1-30)-K6-NH 2 represented by the sequence:
(SEQ ID NO: 12)
H-HGDGSFTDELKTILDNLAARDFIAWLIQTK6-NH 2 ,
said method comprising:
(i) culturing host cells transformed with an expression vector comprising a nucleic acid sequence encoding the GLP-2 analogue under conditions suitable for expressing the GLP-2 analogue; and
(ii) purifying the GLP-2 analogue thus produced.
52 . The method of claim 51 , wherein the host cells are bacterial cells.
53 . A therapeutic kit comprising:
(i) a cancer chemotherapy drug, and
(ii) the glucagon-like peptide 2 (GLP-2) analogue [Gly2, Pro6, Leu10, Ala11, 16,24, 28]hGLP-2-NH 2 represented by the sequence:
(SEQ ID NO: 3)
HGDGSPSDELATILDALAARDFIAWLIATKITD-NH 2 ,
or a pharmaceutically acceptable salt or derivative thereof.
54 . The therapeutic kit of claim 53 , wherein the cancer chemotherapy drug is methotrexate.