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Supplementary Information from Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody–Drug Conjugates with Self-Immolative Disulfide Linkers

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posted on 2023-04-03, 14:42 authored by Thomas H. Pillow, Melissa Schutten, Shang-Fan Yu, Rachana Ohri, Jack Sadowsky, Kirsten Achilles Poon, Willy Solis, Fiona Zhong, Geoffrey Del Rosario, Mary Ann T. Go, Jeffrey Lau, Sharon Yee, Jintang He, Luna Liu, Carl Ng, Keyang Xu, Douglas D. Leipold, Amrita V. Kamath, Donglu Zhang, Luke Masterson, Stephen J. Gregson, Philip W. Howard, Fan Fang, Jinhua Chen, Janet Gunzner-Toste, Katherine K. Kozak, Susan Spencer, Paul Polakis, Andrew G. Polson, John A. Flygare, Jagath R. Junutula

Supplementary Figures S1-S5, Supplementary Materials and Methods

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ARTICLE ABSTRACT

A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody–drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. Mol Cancer Ther; 16(5); 871–8. ©2017 AACR.

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