LONG-ACTING GLP-1/GLUCAGON RECEPTOR AGONISTS
Pegylated and reverse pegylated GLP-1/Glucaron receptor agonists including pharmaceutical compositions comprising the same and methods of using the same are disclosed.
1 . A composition consisting of an oxyntomodulin, a polyethylene glycol polymer (PEG polymer) and 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS).
2 . The composition of claim 1 , wherein said PEG polymer is attached to the amino terminus or lysine residue of said oxyntomodulin via Fmoc or FMS.
3 . The composition of claim 1 , wherein said oxyntomodulin consists of the amino acid sequence set forth in SEQ ID NO: 1.
4 . The composition of claim 1 , wherein said PEG polymer is a PEG polymer with a sulfhydryl moiety.
5 . The composition of claim 1 , wherein said PEG polymer is PEG 30 , PEG 40 or PEG 60 .
6 . A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutical acceptable carrier.
7 . A method for extending the biological half life of oxyntomodulin, consisting of the step of conjugating oxyntomodulin, a polyethylene glycol polymer (PEG polymer) and 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS) in a molar ratio of about 1:1:0.5 to about 1:1:3.5.
8 . The method of claim 7 , wherein said oxyntomodulin consists of an amino acid sequence of SEQ ID NO: 1.
9 . The method of claim 7 , wherein said PEG polymer is conjugated to the amino terminus or lysine residue of said oxyntomodulin via Fmoc or FMS.
10 . The method of claim 7 , wherein said PEG polymer is a PEG polymer with a sulfhydryl moiety.
11 . The method of claim 7 , wherein said PEG polymer is PEG 30 , PEG 40 or PEG 60 .
12 . A method of inducing glucose tolerance, glycemic control, or both in a subject in need thereof, comprising the step of administering to said subject an effective amount of the composition of claim 1 and a pharmaceutical acceptable carrier.
13 . The method of claim 12 , wherein said oxyntomodulin consists of an amino acid sequence of SEQ ID NO: 1.
14 . The method of claim 12 , wherein said PEG polymer is conjugated to the amino terminus or lysine residue of said oxyntomodulin via Fmoc or FMS.
15 . The method of claim 12 , wherein said PEG polymer is a PEG polymer with a sulfhydryl moiety.
16 . The method of claim 12 , wherein said PEG polymer is PEG 30 , PEG 40 or PEG 60 .
17 . A method of improving the area under the curve (AUC) of oxyntomodulin, consisting of the step of conjugating a polyethylene glycol polymer (PEG polymer) to the amino terminus of said oxyntomodulin via 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS).
18 . The method of claim 17 , wherein said oxyntomodulin consists of an amino acid sequence of SEQ ID NO: 1.
19 . The method of claim 17 , wherein said PEG polymer is conjugated to the amino terminus or lysine residue of said oxyntomodulin via Fmoc or FMS.
20 . The method of claim 17 , wherein said PEG polymer is a PEG polymer with a sulfhydryl moiety.
21 . The method of claim 17 , wherein said PEG polymer is PEG 30 , PEG 40 or PEG 60 .
22 . A method of reducing the dosing frequency of oxyntomodulin, consisting of the step of conjugating a polyethylene glycol polymer (PEG polymer) to the amino terminus of said oxyntomodulin via 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS).
23 . The method of claim 22 , wherein said oxyntomodulin consists of an amino acid sequence of SEQ ID NO: 1.
24 . The method of claim 22 , wherein said PEG polymer is conjugated to the amino terminus or lysine residue of said oxyntomodulin via Fmoc or FMS.
25 . The method of claim 22 , wherein said PEG polymer is a PEG polymer with a sulfhydryl moiety.
26 . The method of claim 22 , wherein said PEG polymer is PEG 30 , PEG 40 or PEG 60 .
27 . A method for reducing food intake, reducing body weight, or both in a subject, comprising the step of administering oxyntomodulin conjugated to polyethylene glycol polymer (PEG polymer) via a flexible linker to said subject, wherein said flexible linker is 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS).
28 . The method of claim 27 , wherein said oxyntomodulin consists of an amino acid sequence of SEQ ID NO: 1.
29 . The method of claim 27 , wherein said PEG polymer is conjugated to the amino terminus or lysine residue of said oxyntomodulin via Fmoc or FMS.
30 . The method of claim 27 , wherein said PEG polymer is a PEG polymer with a sulfhydryl moiety.
31 . The method of claim 27 , wherein said PEG polymer is PEG 30 , PEG 40 or PEG 60 .
32 . A method for increasing insulin sensitivity in a subject, comprising the step of administering to the subject an effective amount of a composition comprising oxyntomodulin conjugated to polyethylene glycol polymer (PEG polymer).
33 . The method of claim 32 , wherein said PEG polymer is PEG 30 , PEG 40 or PEG 60 .
34 . The method of claim 32 , wherein said oxyntomodulin is conjugated to said polyethylene glycol polymer (PEG polymer) via a linker.
35 . The method of claim 33 , wherein said linker is a cleavable flexible linker.
36 . The method of claim 33 , wherein the linker is a non-cleavable linker.
37 . The method of claim 35 , wherein said flexible linker is 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS).
38 . The method of claim 36 , wherein said linker is N-(ε-Maleimidocaproyloxu) succinimide ester (EMCS).
39 . The method of claim 32 , wherein administering said composition results in an acute increase in insulin sensitivity in said subject.