Pegylated oxm variants

Abstract

A composition which includes oxyntomodulin and polyethylene glycol polymer (PEG polymer) linked via a reversible linker such as 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS) is disclosed. Pharmaceutical compositions comprising the reverse pegylated oxyntomodulin and methods of using same are also disclosed.

1 . A method of improving the area under the curve (AUC) of oxyntomodulin in a subject in need of treatment therewith, the method comprising administering to said subject an oxyntomodulin conjugate represented by the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         2 . A method of reducing the dosing frequency of oxyntomodulin in a subject in need of treatment therewith, said method comprising administering to said subject an oxyntomodulin conjugate represented by the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A method for extending the biological half-life of oxyntomodulin in a subject in need of treatment therewith, the method comprising administering to said subject an oxyntomodulin conjugate represented by the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 3 , wherein said oxyntomodulin is released into a biological fluid by chemically hydrolyzing the FMS or Fmoc linker from said oxyntomodulin conjugate. 
     
     
         5 . The method of  claim 4 , wherein the released oxyntomodulin is intact and regains GLP-1 and glucagon receptor binding activity. 
     
     
         6 . The method of  claim 4 , wherein said biological fluid is blood, sera, or cerebrospinal fluid. 
     
     
         7 . A method of inducing glucose tolerance, inducing glycemic control, increasing insulin sensitivity, or reducing insulin resistance in a subject in need thereof, the method comprising administering to the subject an oxyntomodulin conjugate represented by the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A method of improving the cholesterol levels in a subject in need thereof, the method comprising administering to the subject an oxyntomodulin conjugate represented by the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A homogeneous intermediate conjugate represented by the structure of: 
       
         
           
           
               
               
           
         
       
       wherein R 2  is H and said His 1  is conjugated to said Fmoc linker or R 2  is SO 3 H and said His 1  is conjugated to said FMS linker; and
 wherein the amino side groups of Lys 12  and Lys 30  of said oxyntomodulin are protected. 
 
     
     
         10 . The conjugate of  claim 9 , wherein said PEG is represented by (CH 2 CH 2 O) n CH 3 , wherein n is 30 (PEG30), 40 (PEG40) or 60 (PEG60). 
     
     
         11 . A homogeneous intermediate conjugate represented by the structure of: 
       
         
           
           
               
               
           
         
       
       wherein R 2  is H and Lys 30  is conjugated to the Fmoc linker or R 2  is SO 3 H and Lys 30  is conjugated to the FMS linker; and
 wherein the terminal amino group of His 1  and the amino side group of Lys 12  of oxyntomodulin are protected. 
 
     
     
         12 . The conjugate of  claim 11 , wherein said PEG is represented by (CH 2 CH 2 O) n CH 3 , wherein n is 30 (PEG30), 40 (PEG40) or 60 (PEG60). 
     
     
         13 . A homogeneous intermediate conjugate represented by the structure of: 
       
         
           
           
               
               
           
         
       
       wherein R 2  is H and Lys 12  is conjugated to the Fmoc linker or R 2  is SO 3 H and Lys 12  is conjugated to the FMS linker; and
 wherein the terminal amino group of His' and the amino side group of Lys 30  of oxyntomodulin are protected. 
 
     
     
         14 . The conjugate of  claim 13 , wherein said PEG is represented by (CH 2 CH 2 O) n CH 3 , wherein n is 30 (PEG30), 40 (PEG40) or 60 (PEG60).