Amphiphilic polymers and polypeptide conjugates comprising same

Abstract

Proteins and/or peptides, such as luminal cholecystokinin releasing factor (LCRF) are conjugated with amphiphilic oligomers and polymers. Such conjugates may modulate the pharmacokinetic profile of the proteins and/or peptides, thereby improving their clinical utility. Such conjugates may also stabilize and deliver the proteins and/or peptides, such as LCRF, to receptors in the gut without absorption into the bloodstream.

1 . A method of providing release of cholecystokinin in a subject, comprising administering to the subject an effective amount of a luminal cholecystokinin releasing factor polypeptide comprising 
 i) a lysine residue;    ii) an oligomeric moiety attached to the N-terminus of the luminal cholecystokinin releasing factor polypeptide; and    iii) an oligomeric moiety attached to the lysine residue,    whereby upon administration to the subject, said compound integrates into a cell membrane of the gut epithelium of the subject wherein the luminal cholecystokinin releasing factor polypeptide binds with a target receptor on the surface of an epithelial cell, thereby providing release of cholecystokinin.    
     
     
         2 . The method of  claim 1 , wherein the oligomeric moiety attached to the N-terminus of the luminal cholecystokinin releasing factor peptide is a branched oligomeric moiety.  
     
     
         3 . The method of  claim 2 , wherein the branched oligomeric moiety has the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 2 , wherein the branched oligomeric moiety has the following formula:  
       
         
           
           
               
               
           
         
         where n is from 3 to 230 and m is from 0 to 20 and X is selected from the group consisting of N, O or S.  
       
     
     
         5 . The method of  claim 2 , wherein the branched oligomeric moiety has a total average molecular weight of 4,000 to 10,000 Daltons.  
     
     
         6 . The method of  claim 1 , wherein the oligomeric moiety is attached to the N-terminus using a hydrolyzable linker.  
     
     
         7 . The method of  claim 2 , wherein the branched oligomeric moiety is attached to the N-terminus using a non-hydrolyzable linker.  
     
     
         8 . The method of  claim 1 , wherein the oligomeric moiety attached to the N-terminus of the luminal cholecystokinin releasing factor polypeptide has a total average molecular weight of 4,000 to 10,000 Daltons.  
     
     
         9 . The method of  claim 1 , wherein the oligomeric moiety is attached to the lysine residue using a hydrolyzable bond.  
     
     
         10 . The method of  claim 1 , wherein the oligomeric moiety attached to the lysine residue is a linear oligomeric moiety.  
     
     
         11 . The method of  claim 10 , wherein the linear oligomeric moiety is attached to the lysine residue using a hydrolyzable bond.  
     
     
         12 . The method of  claim 1 , further comprising a lysine residue at the C-terminus of the luminal cholecystokinin releasing factor polypeptide.  
     
     
         13 . The method of  claim 12 , further comprising a linear oligomeric moiety attached to the lysine residue at the C-terminus of the luminal cholecystokinin releasing factor polypeptide.  
     
     
         14 . A method of treating obesity in a subject comprising administering to the subject an effective amount of a luminal cholecystokinin releasing factor polypeptide comprising 
 i) a lysine residue;    ii) an oligomeric moiety attached to the N-terminus of the luminal cholecystokinin releasing factor polypeptide; and    iii) an oligomeric moiety attached to the lysine residue.    
     
     
         15 . The method of  claim 14 , wherein the oligomeric moiety attached to the N-terminus of the luminal cholecystokinin releasing factor peptide is a branched oligomeric moiety.  
     
     
         16 . The method of  claim 15 , wherein the branched oligomeric moiety has the following formula:  
       
         
           
           
               
               
           
         
         where n is from 3 to 230 and m is from 0 to 20.  
       
     
     
         17 . The method of  claim 15 , wherein the branched oligomeric moiety has the following formula:  
       
         
           
           
               
               
           
         
         where n is from 3 to 230 and m is from 0 to 20 and X is selected from the group consisting of N, O or S.  
       
     
     
         18 . The method of  claim 15 , wherein the branched oligomeric moiety has a total average molecular weight of 4,000 to 10,000 Daltons.  
     
     
         19 . The method of  claim 14 , wherein the oligomeric moiety is attached to the N-terminus using a hydrolyzable linker.  
     
     
         20 . The method of  claim 15 , wherein the branched oligomeric moiety is attached to the N-terminus using a non-hydrolyzable linker.  
     
     
         21 . The method of  claim 14 , wherein the oligomeric moiety attached to the N-terminus of the luminal cholecystokinin releasing factor polypeptide has a total average molecular weight of 4,000 to 10,000 Daltons.  
     
     
         22 . The method of  claim 14 , wherein the oligomeric moiety is attached to the lysine residue using a hydrolyzable bond.  
     
     
         23 . The method of  claim 14 , wherein the oligomeric moiety attached to the lysine residue is a linear oligomeric moiety.  
     
     
         24 . The method of  claim 23 , wherein the linear oligomeric moiety is attached to the lysine residue using a hydrolyzable bond.  
     
     
         25 . The method of  claim 14 , further comprising a lysine residue at the C-terminus of the luminal cholecystokinin releasing factor polypeptide.  
     
     
         26 . The method of  claim 25 , further comprising a linear oligomeric moiety attached to the lysine residue at the C-terminus of the luminal cholecystokinin releasing factor polypeptide.  
     
     
         27 . A method of providing release of cholecystokinin in a subject, comprising administering to the subject an effective amount of a luminal cholecystokinin releasing factor polypeptide comprising 
 i) a first lysine residue;    ii) a second lysine residue at the C-terminus of the luminal cholecystokinin releasing factor polypeptide;    iii) a branched oligomeric moiety attached to the N-terminus of the luminal cholecystokinin releasing factor polypeptide using a non-hydrolyzable linker;    iv) a linear oligomeric moiety attached to the first lysine residue of the luminal cholecystokinin releasing factor polypeptide using a hydrolyzable bond; and    v) a linear oligomeric moiety attached to the second lysine residue at the C-terminus of the luminal cholecystokinin releasing factor polypeptide,    whereby, upon administration to the subject, said compound integrates into a cell membrane of the gut epithelium of the subject wherein the luminal cholecystokinin releasing factor polypeptide binds with a target receptor on the epithelial cell surface, thereby providing release of cholecystokinin.    
     
     
         28 . The method of  claim 27 , wherein the branched oligomeric moiety has the following formula:  
       
         
           
           
               
               
           
         
         where n is from 3 to 230 and m is from 0 to 20.  
       
     
     
         29 . The method of  claim 27 , wherein the branched oligomeric moiety has the following formula:  
       
         
           
           
               
               
           
         
         where n is from 3 to 230 and m is from 0 to 20 and X is selected from the group consisting of N, O or S.  
       
     
     
         30 . The method of  claim 27 , wherein the branched oligomeric moiety has a total average molecular weight of 4,000 to 10,000 Daltons.  
     
     
         31 . A method of treating obesity in a subject, comprising administering to the subject an effective amount of a luminal cholecystokinin releasing factor polypeptide comprising 
 i) a first lysine residue;    ii) a second lysine residue at the C-terminus of the luminal cholecystokinin releasing factor polypeptide;    iii) a branched oligomeric moiety attached to the N-terminus of the luminal cholecystokinin releasing factor polypeptide using a non-hydrolyzable linker;    iv) a linear oligomeric moiety attached to the first lysine residue of the luminal cholecystokinin releasing factor polypeptide using a hydrolyzable bond; and    v) a linear oligomeric moiety attached to the second lysine residue at the C-terminus of the luminal cholecystokinin releasing factor polypeptide.    
     
     
         32 . The method of  claim 31 , wherein the branched oligomeric moiety has the following formula:  
       
         
           
           
               
               
           
         
         where n is from 3 to 230 and m is from 0 to 20.  
       
     
     
         33 . The method of  claim 31 , wherein the branched oligomeric moiety has the following formula:  
       
         
           
           
               
               
           
         
         where n is from 3 to 230 and m is from 0 to 20 and X is selected from the group consisting of N, O or S.  
       
     
     
         34 . The method of  claim 31 , wherein the branched oligomeric moiety has a total average molecular weight of 4,000 to 10,000 Daltons.  
     
     
         35 . A method of treating obesity in a subject comprising administering to the subject an effective amount of a compound selected from the group consisting of: 
 a) A compound of the formula:                           where n is from 3 to 230 and m is from 0 to 20;    b) A compound of the formula:                           where n is from 3 to 230 and m is from 0 to 20 and X is selected from the group consisting of N, O or S;    c) A compound of the formula:                           where n is from 3 to 230 and m is from 0 to 20; and    d) A compound of the formula:                           where n is from 3 to 230 and m is from 0 to 20 and X is selected from the group consisting of N, O or S;    and any combination thereof.