Long lasting insulin derivatives and methods thereof
The present invention relates to an insulin derivative comprising an insulin molecule and a reactive group for covalently bonding a blood component, wherein preferably the insulin molecule is human natural insulin molecule and the reactive group is coupled to an amino acid of the insulin molecule at a position selected from the positions Gly A1, Phe B1 and Lys B29.
1 . An insulin derivative comprising an insulin molecule and a reactive group for covalently bonding a blood component.
2 . The insulin derivative of claim 1 , wherein the insulin molecule is of formula I:
and the reactive group is coupled to an amino acid of the insulin molecule at a position selected from the positions Gly A1, Phe B1 and Lys B29.
3 . The insulin derivative of claim 1 or 2 , wherein the reactive group is selected from the group consisting of Michael acceptor, a succinimidyl-containing group and a maleimido-containing group.
4 . The insulin derivative of claim 3 , wherein the Michael acceptor is an α,β, unsaturated carbonyl moiety.
5 . The insulin derivative of claim 1 or 2 , wherein the reactive group is a maleimido-containing group.
6 . The insulin derivative of claim 1 or 2 , wherein the reactive group is 3-Maleimidopropionic acid (MPA).
7 . The insulin derivative of any one of claims 1 to 6 , wherein the reactive group is coupled to an amino acid of the insulin molecule via a linker.
8 . The insulin derivative of claim 7 , wherein said linker is selected from the group consisting of (2-amino) ethoxy acetic acid (AEA), ethylenediamine (EDA), amino ethoxy ethoxy succinimic acid (AEES), AEES-AEES, 2-[2-(2-amino)ethoxy)] ethoxy acetic acid (AEEA), AEEA-AEEA, —NH 2 —(CH 2 ) n —COOH where n is an integer between 1 and 20 and alkyl chain (C1-C10) motif and combination thereof.
9 . The insulin derivative of claim 8 , wherein said alkyl chain (C1-C10) motif is one or more alkyl chains (C1-C10) saturated or unsaturated in which could be incorporated oxygen nitrogen or sulfur atoms.
10 . The insulin derivative of claim 9 , wherein said alkyl chain is selected from the group consisting of glycine, 3-aminopropionic acid (APA), 8-aminooctanoic acid (AOA) and 4-aminobenzoic acid (APhA).
11 . The insulin derivative of claim 8 , wherein said combination is selected from the group consisting of AEEA-EDA, AEEA-AEEA and AEA-AEEA.
12 . The insulin derivative of claim 6 , wherein said linker is —NH 2 —(CH 2 ) 7 —COOH.
13 . The insulin derivative of claim 1 having the formula:
14 . The insulin derivative of claim 1 , having the formula:
15 . The insulin derivative of claim 1 , having the formula:
16 . The insulin derivative of claim 1 , wherein said blood component is a blood protein.
17 . The insulin derivative of claim 16 , wherein said blood protein is serum albumin.
18 . An insulin conjugate comprising an insulin derivative according to any one of claims 1 to 17 and a blood component, wherein the reactive group and the blood component are conjugated through a covalent bond formed between said reactive group and said blood component.
19 . The insulin conjugate of claim 18 , wherein the blood component is a blood protein.
20 . The insulin conjugate of claim 19 , wherein the blood protein is serum albumin.
21 . The insulin conjugate of claim 18 , wherein said conjugate was formed ex vivo.
22 . A pharmaceutical composition comprising the insulin derivative of any one of claims 1 to 17 in association with a pharmaceutically acceptable carrier.
23 . A pharmaceutical composition comprising the insulin conjugate of any one of claims 18 to 21 in association with a pharmaceutically acceptable carrier.
24 . A method for treating a glycaemic-related disease or disorder in a subject suffering from said glycaemic-related disease or disorder, comprising administering the insulin derivative of any one of claims 1 to 17 to said subject.
25 . The method according to claim 24 , wherein said glycaemic-related disease is selected from the group consisting of diabetes of type I, diabetes of type II, gestational diabetes, cystic fibrosis, polycystic ovary syndrome and pancreatitis.
26 . The method according to claim 24 , wherein the glycaemic-related disease is selected from the group consisting of diabetes of type I and diabetes of type II.
27 . A method for treating a glycaemic-related disease or disorder, comprising the administration of the insulin conjugate of any one of claims 18 to 21 .
28 . The method according to claim 27 , wherein said glycaemic-related disease is selected from the group consisting of diabetes of type I, diabetes of type II, gestational diabetes, cystic fibrosis, polycystic ovary syndrome and pancreatitis.
29 . The method according to claim 27 , wherein the glycaemic-related disease is selected from the group consisting of diabetes of type I and diabetes of type II.
30 . A method for treating a glycaemic-related disease or disorder, comprising the administration of the pharmaceutical composition of any one of claims 22 and 23 .
31 . The method according to claim 30 , wherein said glycaemic-related disease is selected from the group consisting of diabetes of type I, diabetes of type II, gestational diabetes, cystic fibrosis, polycystic ovary syndrome and pancreatitis.
32 . The method according to claim 30 , wherein the glycaemic-related disease is selected from the group consisting of diabetes of type I and diabetes of type II.
33 . Use of the derivative of any one of claims 1 to 17 , for the preparation of a medicament for the treatment of a glycaemic-related disease or disorder.
34 . The use as claimed in claim 33 , wherein said glycaemic-related disease is selected from the group consisting of diabetes of type I, diabetes of type II, gestational diabetes, cystic fibrosis, polycystic ovary syndrome and pancreatitis.
35 . The use as claimed in claim 33 , wherein the glycaemic-related disease is selected from the group consisting of diabetes of type I and diabetes of type II.
36 . Use of the conjugate of any one of claims 18 to 19 , for the preparation of a medicament for the treatment of a glycaemic-related disease or disorder.
37 . The use as claimed in claim 36 , wherein said glycaemic-related disease is selected from the group consisting of diabetes of type I, diabetes of type II, gestational diabetes, cystic fibrosis, polycystic ovary syndrome and pancreatitis.
38 . The use as claimed in claim 37 , wherein the glycaemic-related disease is selected from the group consisting of diabetes of type I and diabetes of type II.