Protein-polymer-drug conjugates

Abstract

A polymeric scaffold useful for conjugating with a protein based recognition-molecule (PBRM) to form a PBRM-polymer-drug conjugate is described herein. The scaffold includes one or more terminal maleimido groups. Also disclosed is a PBRM-polymer-drug conjugate prepared from the scaffold. Compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions are also described.

What is claimed is: 
     
         1 . A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a polymer drug conjugate of Formula (Ie): 
       
         
           
           
               
               
           
         
       
       wherein:
 the polymer drug conjugate comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from about 2 kDa to about 40 kDa, and wherein the disconnection between the monomeric units indicates that the units are randomly arranged; 
 each occurrence of D independently is a therapeutic agent having a molecular weight of ≤5 kDa, and the 
 
       
         
           
           
               
               
           
         
       
       between D and the carbonyl group denotes direct or indirect attachment of D to the carbonyl group,
 X is CH 2 , O, or NH; 
 PBRM has a molecular weight of greater than 40 kDa; 
 one of X a  and X b  is H and the other is a maleimido blocking moiety, or X a  and X b , together with the carbon atoms to which they are attached form a carbon-carbon double bond; 
 m 1  is an integer from 1 to about 300, 
 m 1  is an integer from 1 to about 140, 
 m 2  is an integer from 1 to about 40, 
 m 7  is an integer from 1 to about 40, 
 m 3a  is an integer from 0 to about 17, 
 m 3b  is an integer from 1 to about 8, wherein the sum of m 3a  and m 3b  is m 3 , 
 the sum of m, m 1 , m 7 , m 3a , and m 3b  ranges from about 15 to about 300, and 
 m 5  is an integer from 1 to about 10. 
 
     
     
         2 . The method of  claim 1 , wherein the PHF has a molecular weight ranging from about 2 kDa to about 20 kDa, m 1  is an integer from 1 to about 70, m 2  is an integer from 1 to about 20, m 7  is an integer from 1 to about 20, m 5  is an integer from 2 to about 8, m 3a  is an integer from 0 to about 9, m 3b  is an integer from 1 to about 8, and the sum of m, m 1 , m 7 , m 3a , and m 3b  ranges from about 15 to about 150. 
     
     
         3 . The method of  claim 1 , wherein the PHF has a molecular weight ranging from about 3 kDa to about 15 kDa, m 1  is an integer from 2 to about 50, m 2  is an integer from 2 to about 15, m 7  is an integer from 2 to about 15, m 5  is an integer from 2 to about 4, m 3a  is an integer from 0 to about 7, m 3b  is an integer from 1 to about 8, and the sum of m, m 1 , m 3  and m 7  ranges from about 20 to about 110. 
     
     
         4 . The method of  claim 1 , wherein the PHF has a molecular weight ranging from about 5 kDa to about 10 kDa, m 1  is an integer from 5 to about 35, m 2  is an integer from 2 to about 10, m 7  is an integer from 3 to about 10, m 5  is an integer from 2 to about 4, m 3a  is an integer from 0 to about 4, m 3b  is an integer from 1 to about 5, and the sum of m, m 1 , m 3  and m 7  ranges from about 40 to about 75. 
     
     
         5 . The method of  claim 1 , wherein m 5  is an integer from about 2 to about 4. 
     
     
         6 . The method of  claim 1 , wherein the ratio between m 7  and m 3b  is greater than 1:1 and less than or equal to 10:1. 
     
     
         7 . The method of  claim 6 , wherein the ratio between m 7  and m 3b  is between 2:1 and 8:1. 
     
     
         8 . The method of  claim 7 , wherein the ratio between m 7  and m 3b  is between 2:1 and and 4:1. 
     
     
         9 . The method of  claim 1 , wherein each occurrence of D independently is selected from the group consisting of an auristatin compound, a topoisomerase inhibitor, a calicheamicin compound, a vinca compound, a tubulysin compound, a duocarmycin compound, a pyrrolobenzodiazepine compound, a kinase inhibitor, a KSP inhibitor, a maytansinoid, a DNA-binding, alkylating or intercalating drug, a RNA polymerase inhibitor, a protein synthesis inhibitor, and analogs thereof. 
     
     
         10 . The method of  claim 9 , wherein each occurrence of D independently is selected from the group consisting of an auristatin compound, a topoisomerase inhibitor, a calicheamicin compound, a tubulysin compound, a duocarmycin compound, a pyrrolobenzodiazepine compound, and analogs thereof. 
     
     
         11 . The method of  claim 10 , the auristatin compound is auristatin, dolastatin, monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), auristatin F, AF HPA, or auristatin phenylenediamine (AFP). 
     
     
         12 . The method of  claim 1 , wherein the polymer drug conjugate is of Formula (Ib): 
       
         
           
           
               
               
           
         
         wherein the sum of m, m 1 , m 2 , m 3a , and m 3b  ranges from about 15 to about 300; and 
         m 5  is an integer from 1 to about 10. 
       
     
     
         13 . The method of  claim 12 , wherein the PHF has a molecular weight ranging from about 2 kDa to about 20 kDa, the sum of m, m 1 , m 2 , m 3a  and m 3b  ranges from about 15 to about 150, m 1  is an integer from 1 to about 70, m 2  is an integer from 1 to about 20, m 3a  is an integer from 0 to about 9, m 3b  is an integer from 1 to about 8, and m 5  is an integer from 2 to about 8. 
     
     
         14 . The method of  claim 12 , wherein the PHF has a molecular weight ranging from about 3 kDa to about 15 kDa, the sum of m, m 1 , m 2 , m 3a  and m 3b  ranges from about 20 to about 110, m 1  is an integer from 2 to about 50, m 2  is an integer from 2 to about 15, m 3a  is an integer from 0 to about 7, m 3b  is an integer from 1 to about 8, and m 5  is an integer from 2 to about 4. 
     
     
         15 . The method of  claim 12 , wherein the PHF has a molecular weight ranging from about 5 kDa to about 10 kDa, the sum of m, m 1 , m 2 , m 3a  and m 3b  ranges from about 40 to about 75, m 1  is an integer from about 5 to about 35, m 2  is an integer from about 3 to about 10, m 3a  is an integer from 0 to about 4, m 3b  is an integer from 1 to about 5, and m 5  is an integer from 2 to about 4. 
     
     
         16 . The method of  claim 12 , wherein the polymer drug conjugate is of Formula (B): 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 16 , wherein the PHF has a molecular weight ranging from 5 kDa to 10 kDa, the sum of m, m 1 , m 2 , m 3a , and m 3b  ranges from about 40 to about 75, m is an integer from 1 to 75, m 1  is an integer from about 5 to about 35, m 2  is an integer from about 3 to about 10, m 3a  is an integer from 0 to about 4, m 3b  is an integer from 1 to about 5, and m 5  is an integer from 2 to about 4. 
     
     
         18 . The method of  claim 12 , wherein the polymer drug conjugate is of Formula (B1): 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 18 , wherein the PHF has a molecular weight ranging from 5 kDa to 10 kDa, the sum of m, m 1 , m 2 , m 3a , and m 3b  ranges from about 40 to about 75, m is an integer from 1 to 75, m 1  is an integer from about 5 to about 35, m 2  is an integer from about 3 to about 10, m 3a  is an integer from 0 to about 4, m 3b  is an integer from 1 to about 5, and m 5  is an integer from 2 to about 4.