title: Expanded Utility of the β-Glucuronide Linker: ADCs That Deliver Phenolic Cytotoxic Agents.
abstract: The β-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 β-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 β-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.
authors.affiliation: Seattle Genetics, 21823 30th Drive SE, Bothell, Washington 98021.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
authors.affiliation: Department of Biochemistry and Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038.
authors.forename: Jef
authors.initials: J
authors.lastname: De Brabander
authors.affiliation: Seattle Genetics, 21823 30th Drive SE, Bothell, Washington 98021.
authors.forename: Jamie
authors.initials: J
authors.lastname: Miyamoto
authors.affiliation: Seattle Genetics, 21823 30th Drive SE, Bothell, Washington 98021.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
keywords: CD30-positive L540cy cell line; CD70-positive Caki-1 cell line; N,N′-dimethylethylene diamine; antibody−drug conjugates; phenolic cytotoxic agents; β-Glucuronide linker