title: Linker Immolation Determines Cell Killing Activity of Disulfide-Linked Pyrrolobenzodiazepine Antibody-Drug Conjugates.
abstract: Disulfide bonds could be valuable linkers for a variety of therapeutic applications requiring tunable cleavage between two parts of a molecule (e.g., antibody-drug conjugates). The in vitro linker immolation of β-mercaptoethyl-carbamate disulfides and DNA alkylation properties of associated payloads were investigated to understand the determinant of cell killing potency of anti-CD22 linked pyrrolobenzodiazepine (PBD-dimer) conjugates. Efficient immolation and release of a PBD-dimer with strong DNA alkylation properties were observed following disulfide cleavage of methyl- and cyclobutyl-substituted disulfide linkers. However, the analogous cyclopropyl-containing linker did not immolate, and the associated thiol-containing product was a poor DNA alkylator. As predicted from these in vitro assessments, the related anti-CD22 ADCs showed different target-dependent cell killing activities in WSU-DLCL2 and BJAB cell lines. These results demonstrate how the in vitro immolation models can be used to help design efficacious ADCs.
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Pillow
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Josefa Dela
authors.initials: JD
authors.lastname: Cruz-Chuh
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Kozak
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Sadowsky
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Lewis Phillips
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Martine
authors.initials: M
authors.lastname: Darwish
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Fan
authors.affiliation: Wuxi Apptec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Jingtian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Wuxi Apptec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Changrong
authors.initials: C
authors.lastname: He
authors.affiliation: Wuxi Apptec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Wuxi Apptec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: Wuxi Apptec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Zijin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Wuxi Apptec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Wuxi Apptec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: John
authors.initials: J
authors.lastname: Wai
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
authors.affiliation: Drug Metabolism & Pharmacokinetics, Discovery Chemistry, Biochemical and Cellular Pharmacology, Protein Chemistry, and Molecular Oncology, Genentech , South San Francisco, California 94080, United States.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
keywords: Antibody−drug conjugate; cancer; disulfide linker; linker immolation; pyrrolobenzodiazepine