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Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization.


ABSTRACT: Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using noncleavable linkers, and the resulting conjugates (ADC-4 and ADC-10) led to in vivo efficacy in an HER-2 expressing (SK-OV-3ip) mouse xenograft model while ADC-11 led to in vivo efficacy in an anti-c-KIT (NCI-H526) mouse xenograft model in a target-dependent manner.

SUBMITTER: Karpov AS 

PROVIDER: S-EPMC6912867 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization.

Karpov Alexei S AS   Nieto-Oberhuber Cristina M CM   Abrams Tinya T   Beng-Louka Edwige E   Blanco Enrique E   Chamoin Sylvie S   Chene Patrick P   Dacquignies Isabelle I   Daniel Dylan D   Dillon Michael P MP   Doumampouom-Metoul Lionel L   Drosos Nikolaos N   Fedoseev Pavel P   Furegati Markus M   Granda Brian B   Grotzfeld Robert M RM   Hess Clark Suzanna S   Joly Emilie E   Jones Darryl D   Lacaud-Baumlin Marion M   Lagasse-Guerro Stephanie S   Lorenzana Edward G EG   Mallet William W   Martyniuk Piotr P   Marzinzik Andreas L AL   Mesrouze Yannick Y   Nocito Sandro S   Oei Yoko Y   Perruccio Francesca F   Piizzi Grazia G   Richard Etienne E   Rudewicz Patrick J PJ   Schindler Patrick P   Velay Mélanie M   Venstrom Kristine K   Wang Peiyin P   Zurini Mauro M   Lafrance Marc M  

ACS medicinal chemistry letters 20191203 12


Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from  ...[more]

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