Acryloyloxyethylphosphorylcholine Containing Polymer Conjugates And Their Preparation

Abstract

The present invention relates to polymeric reagents and conjugates thereof, methods for synthesizing the polymeric reagents and conjugates, pharmaceutical compositions comprising the conjugates and methods of using the polymer conjugates including therapeutic methods where conjugates are administered to patients.

1 - 40 . (canceled) 
     
     
         41 . A compound comprising a biologically active protein covalently bonded to a phosphorylcholine containing polymer, wherein said polymer is branched, having 2 or more polymer arms, wherein each polymer arm is represented by the formula: 
       
         
           
           
               
               
           
         
         wherein m is about 100 to about 2000; 
         each occurrence of E is independently selected from the group consisting of halo; 
         each occurrence of Q is independently selected from the group consisting of H, methyl and ethyl; and 
         each occurrence of T is independently —C 1-4  alkyl-phosphorylcholine. 
       
     
     
         42 . The compound of  claim 41  wherein Q is methyl. 
     
     
         43 . The compound of  claim 44  wherein T is —CH 2 —CH 2 -phosphorylcholine. 
     
     
         44 . The compound of  claim 41  wherein m is about 100 to about 500. 
     
     
         45 . The compound of  claim 41  wherein m is about 500 to about 1000. 
     
     
         46 . The compound of  claim 41  wherein the polymer has 2, 3, 4, 5, 6, 7 or 8 polymer arms. 
     
     
         47 . The compound of  claim 46  wherein the polymer has 3 arms. 
     
     
         48 . The compound of  claim 46  wherein the polymer has 6 arms. 
     
     
         49 . The compound of  claim 41  wherein the polymer has more than 8 arms. 
     
     
         50 . The compound of  claim 41  wherein the phosphorylcholine containing polymer is covalently bonded to at least an amino group, a hydroxyl group, a sulfhydryl group or a carboxyl group of the biologically active protein. 
     
     
         51 . The compound of  claim 41  wherein the biologically active protein is a human protein. 
     
     
         52 . The compound of  claim 51  wherein the human protein is obtained by heterologous gene expression in a cell selected from the group consisting of a bacterium, a yeast cell, a mammalian cell in culture, an insect cell in culture, a plant cell in culture, an avian cell in culture, a cell of a transgenic avian, a cell of a transgenic mammal, and a cell of a transgenic plant. 
     
     
         53 . The compound of  claim 41  wherein the biologically active protein is selected from the group consisting of a cytokine, an enzyme, an antibody and an antibody fragment. 
     
     
         54 . The compound of  claim 41 , wherein the polymer portion of the compound is polydisperse. 
     
     
         55 . The compound of  claim 54 , wherein the polymer portion has a polydispersity value in the range of about 1.4 to about 1.2. 
     
     
         56 . The compound of  claim 55 , wherein the polymer portion has a polydispersity value of less than about 1.15. 
     
     
         57 . The compound of  claim 41  wherein m is about 200 to about 2000. 
     
     
         58 . A pharmaceutical composition comprising the compound of  claim 41  in a liquid solution. 
     
     
         59 . A pharmaceutical composition comprising the compound of  claim 43  in a liquid solution. 
     
     
         60 . A pharmaceutical composition comprising the compound of  claim 53  in a liquid solution. 
     
     
         61 . A pharmaceutical composition comprising the compound of  claim 55  in a liquid solution.