Protein-polymer-drug conjugates

摘要

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.

主权项

1. A polymeric scaffold of Formula (Ia) useful to conjugate with a protein based recognition-molecule (PBRM) that has a molecular weight of less than 80 kDa: wherein: the scaffold comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from 20 kDa to 150 kDa; each occurrence of D is independently a therapeutic agent having a molecular weight of ≦5 kDa; LD1 is a carbonyl-containing moiety; each occurrence ofinis independently a first linker that contains a biodegradable bond so that when the bond is broken, D is released in an active form for its intended therapeutic effect; and theinbetween LD1 and D denotes direct or indirect attachment of D to LD1;
each occurrence ofis independently a second linker not yet connected to the PBRM, in which LP2 is a moiety containing a functional group that is yet to form a covalent bond with a functional group of a PBRM, and thebetween LD1 and LP2 denotes direct or indirect attachment of LP2 to LD1, and each occurrence of the second linker is distinct from each occurrence of the first linker;
m is an integer from 1 to 1100, m1 is an integer from 1 to 330, m2 is an integer from 3 to 150, m3 is an integer from 1 to 55, and the sum of m, m1, m2 and m3 ranges from 150 to about 1100.