Expanded Utility of the β-Glucuronide Linker: ADCs That Deliver Phenolic Cytotoxic Agents

The beta-glucuronide linker has been used for antibody drug conjugates (ADCs) to deliver amine-containing cytotoxic agents. The linker is stable in circulation, hydrophilic and provides ADCs that are highly active in vitro and in vivo. To extend the utility of the beta-glucuronide linker, toward phenol-containing drugs, an N,N '-dimethylethylene diamine self-immolative spacer was incorporated with the linker for release of the potent cytotoxic phenol psymberin A. Exposure of the drug-linker to beta-glucuronidase resulted in facile drug release. The corresponding ADCs were active and immunologically selective against CD30-positive L540cy and CD70-positive Caki-1 cell lines.