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Antibody–Drug Conjugates with Pyrrole‐Based KSP Inhibitors as the Payload Class
Author(s) -
Lerchen HansGeorg,
Wittrock Sven,
StelteLudwig Beatrix,
Sommer Anette,
Berndt Sandra,
Griebenow Nils,
Rebstock AnneSophie,
Johannes Sarah,
CanchoGrande Yolanda,
Mahlert Christoph,
Greven Simone,
Terjung Carsten
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201807619
Subject(s) - payload (computing) , in vivo , linker , drug , computational biology , mode of action , conjugate , chemistry , computer science , cancer research , pharmacology , medicine , biology , biochemistry , computer network , mathematical analysis , microbiology and biotechnology , mathematics , network packet , operating system
The number of cytotoxic payload classes successfully employed in antibody–drug conjugates (ADCs) is still rather limited. The identification of ADC payloads with a novel mode of action will increase therapeutic options and potentially increase the therapeutic window. Herein, we describe the utilization of kinesin spindle protein inhibitors (KSPi) as a novel payload class providing highly potent ADCs against different targets, for instance HER‐2 or TWEAKR/Fn14. Aspects of technical optimization include the development of different linker attachment sites, the stabilization of ADC linkage to avoid payload deconjugation and finally, the tailor‐made design of active metabolites with a long lasting intracellular exposure in the tumor matching the mode of action of KSP inhibition. These KSPi‐ADCs are highly potent and selective in vitro and demonstrate in vivo efficacy in a broad panel of tumor models including complete regressions in a patient‐derived urothelial cancer model.