Protein-polymer-drug conjugates

Abstract

A drug conjugate is provided herein. The conjugate comprises a protein based recognition-molecule (PBRM) and a polymeric carrier substituted with one or more -LD-D, the protein based recognition-molecule being connected to the polymeric carrier by LP. Each occurrence of D is independently a therapeutic agent having a molecular weight ≤5 kDa. LD and LP are linkers connecting the therapeutic agent and PBRM to the polymeric carrier respectively. Also disclosed are polymeric scaffolds useful for conjugating with a PBRM to form a polymer-drug-PBRM conjugate described herein, compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions.

What is claimed is: 
     
         1 . A polymeric scaffold having Formula (Id): 
       
         
           
           
               
               
           
         
       
       wherein:
 the polymeric scaffold comprises poly(l-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from 2 kDa to 40 kDa; 
 each L D1  is independently a carbonyl-containing moiety; 
 each L P2  is independently a moiety containing a functional group that is capable of 
 
       forming a covalent bond with a functional group of the PBRM, and the 
       
         
           
           
               
               
           
         
       
       between L D1  and L P2  denotes direct or indirect attachment of L P2  to L D1 ;
 m 1  is an integer from 1 to about 140; 
 m 3  is an integer from 1 to about 18; and 
 the sum of m, m 1 , and m 3  ranges from about 15 to about 300. 
 
     
     
         2 . The scaffold of  claim 1 , wherein m 1  is an integer from 2 to about 120. 
     
     
         3 . The scaffold of  claim 1 , wherein the PHF has a molecular weight ranging from 6 kDa to 20 kDa; m 1  is an integer from 1 to 75; m 3  is an integer from 1 to 9; and the sum of m, m 1  and m 3  is an integer from 45 to 150. 
     
     
         4 . The scaffold of  claim 3 , wherein m 1  is an integer from 6 to about 60. 
     
     
         5 . The scaffold of  claim 1 , wherein the PHF has a molecular weight ranging from 8 kDa to 15 kDa; m 1  is an integer from 1 to 55; m 3  is an integer from 1 to 7; and the sum of m, m 1  and m 3  is an integer from 60 to 110. 
     
     
         6 . The scaffold of  claim 6 , wherein mi is an integer from 6 to about 45. 
     
     
         7 . The scaffold of  claim 1 , wherein the functional group of L P2  is selected from —SR p , —S—S-LG, maleimido, and halo, in which LG is a leaving group and R p  is H or a sulfur protecting group. 
     
     
         8 . The scaffold of  claim 1 , wherein L D1  comprises —X—(CH 2 ) v —C(═O)— with X directly connected to the carbonyl group of 
       
         
           
           
               
               
           
         
       
       in which X is CH 2 , O, or NH, and v is an integer from 1 to 6. 
     
     
         9 . The scaffold of  claim 1 , wherein L P2  contains a biodegradable bond. 
     
     
         10 . The scaffold of  claim 1 , wherein each 
       
         
           
           
               
               
           
         
       
       comprises a terminal group W P , in which each W P  independently is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in which R 1K  is a leaving group; R 1A  is a sulfur protecting group; ring A is cycloalkyl or heterocycloalkyl; and R 1J  is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety. 
       
     
     
         11 . The scaffold of  claim 10 , wherein R 1A  is 
       
         
           
           
               
               
           
         
       
       in which r is 1 or 2 and each of R s1 , R s2 , and R s3  is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety. 
     
     
         12 . A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a PBRM-drug conjugate comprising a polymeric scaffold being conjugated to a protein based recognition-molecule (PBRM) and a therapeutic agent, wherein:
 the polymeric scaffold has Formula (Id):   
       
         
           
           
               
               
           
         
         wherein:
 the polymeric scaffold comprises poly(l-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from 2 kDa to 40 kDa; 
 each L D1  is independently a carbonyl-containing moiety; 
 each L P2  is independently a moiety containing a functional group that is capable of forming a covalent bond with a functional group of the PBRM, and the 
 
       
       
         
           
           
               
               
           
         
       
       between L D1  and L P2  denotes direct or indirect attachment of L P2  to L D1 ;
 m 1  is an integer from 1 to about 140; 
 m 3  is an integer from 1 to about 18; and 
 the sum of m, m 1 , and m 3  ranges from about 15 to about 300; 
 each occurrence of the PBRM is conjugated to the polymeric scaffold via one of L P2 ; and 
 each occurrence of the therapeutic agent is conjugated to the polymeric scaffold via one of L D1 . 
 
     
     
         13 . A method of preparing a polymeric scaffold having Formula (Id): 
       
         
           
           
               
               
           
         
         wherein:
 the polymeric scaffold comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from 2 kDa to 40 kDa; 
 each L D1  is independently a carbonyl-containing moiety; 
 each L P2  is independently a moiety containing a functional group that is capable of forming a covalent bond with a functional group of the PBRM, and the 
 
       
       
         
           
           
               
               
           
         
       
       between L D1  and L P2  denotes direct or indirect attachment of L P2  to L D1 ;
   m 1  is an integer from 1 to about 140;   m 3  is an integer from 1 to about 18; and   the sum of m, m 1 , and m 3  ranges from about 15 to about 300;   
 wherein the method comprises:(a) providing a PHF carrier that is substituted with one or more —C(═O)-L D1 , wherein L D1  is a carbonyl-containing moiety; and 
 (b) reacting the PHF carrier with a compound containing an L P2  moiety to produce a polymeric carrier substituted with one or more 
 
       
         
           
           
               
               
           
         
       
       in which L P2  is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of the PBRM, and 
       
         
           
           
               
               
           
         
       
       denotes direct or indirect attachment of L P2  to L D1 .