Polymer conjugates of therapeutic peptides

Abstract

The invention provides peptides that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the characteristics of the peptide not attached to the water-soluble oligomer.

1 . A conjugate comprising a therapeutic peptide moiety covalently attached, either directly or through a spacer moiety of one or more atoms, to a water-soluble, non-peptidic polymer; wherein:
 the therapeutic peptide is Human Opioid Growth Factor (SEQ. ID. NO. 283); and   the water-soluble, non-peptidic polymer is a poly(alkylene oxide).   
     
     
         2 . A conjugate of  claim 1 , wherein the polymer is a linear polymer. 
     
     
         3 . A conjugate of  claim 1 , wherein the polymer is a branched polymer. 
     
     
         4 - 7 . (canceled) 
     
     
         8 . The conjugate of  claim 1 , wherein the poly(alkylene oxide) is a poly(ethylene glycol). 
     
     
         9 . The conjugate of  claim 8 , wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy. 
     
     
         10 . The conjugate of  claim 8 , wherein the poly(ethylene glycol) has a weight-average molecular weight in a range of from about 500 Daltons to about 100,000 Daltons. 
     
     
         11 . The conjugate of  claim 10 , wherein the poly(ethylene glycol) has a weight-average molecular weight in a range of from about 2000 Daltons to about 50,000 Daltons. 
     
     
         12 . The conjugate of  claim 11 , wherein the poly(ethylene glycol) has a weight-average molecular weight in a range of from about 5000 Daltons to about 40,000 Daltons. 
     
     
         13 . The conjugate of  claim 1 , wherein the water-soluble, non-peptidic polymer is conjugated at an amino-terminal amino acid of the therapeutic peptide moiety. 
     
     
         14 . The conjugate of  claim 1 , wherein the water-soluble, non-peptidic polymer is conjugated at a carboxy-terminal amino acid of the therapeutic peptide moiety. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The conjugate of  claim 8 , wherein the conjugate is formed by reacting a polymeric reagent with the therapeutic peptide, wherein the polymeric reagent has the following structure: 
       
         
           
           
               
               
           
         
         wherein, (n) is independently an integer having a value of from about 2 to about 4000. 
       
     
     
         18 . (canceled) 
     
     
         19 . The conjugate of  claim 8 , wherein the conjugate is formed by reacting a polymeric reagent with the therapeutic peptide, wherein the polymeric reagent has the following structure: 
       
         
           
           
               
               
           
         
         wherein, (n) is independently an integer having a value of from about 2 to about 4000. 
       
     
     
         20 . The conjugate of  claim 1 , wherein the therapeutic peptide residue is covalently attached through a spacer moiety of one or more atoms. 
     
     
         21 . The conjugate of  claim 20 , wherein the spacer moiety includes an amine linkage. 
     
     
         22 . The conjugate of  claim 20 , wherein the spacer moiety includes an amide linkage. 
     
     
         23 . (canceled) 
     
     
         24 . The conjugate of  claim 1 , wherein the therapeutic peptide residue is covalently attached via a stable linkage. 
     
     
         25 . The conjugate of  claim 1 , wherein the therapeutic peptide residue is covalently attached via a releasable linkage. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . A pharmaceutical composition comprising a conjugate of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         29 . (canceled) 
     
     
         30 . A method of treatment comprising administering a conjugate of  claim 1  to a subject in need thereof. 
     
     
         31 . The conjugate of  claim 1 , wherein the conjugate is formed by reacting an mPEG-epoxide with the therapeutic peptide. 
     
     
         32 . The conjugate of  claim 31 , wherein the mPEG-epoxide has a molecular weight of about 5 kD.