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

Karpov, Alexei and Nieto-Oberhuber, Cristina and Grotzfeld, Robert and Abrams, Tinya and Beng-Louka, Edwige and Chamoin, Sylvie and Chene, Patrick and Clark, Suzy and Dacquignies, Isabelle and Doumampouom Metoul, Lionel and Furegati, Markus and Granda, Brian and Joly, Emilie and Jones, Darryl and Lacaud-Baumlin, Marion and Guerro-Lagasse, Stephanie and Lorenzana, Edward and Martyniuk, Piotr and Marzinzik, Andreas and Mesrouze, Yannick and Nocito, Sandro and Oei, Yoko and Perruccio, Francesca and Richard, Etienne and Schindler, Patrick and Velay, Melanie and Venstrom, Kristine and Lafrance, Marc and Blanco, Enrique and Daniel, Dylan and Dillon, Michael and Drosos, Nikolaos and Fedoseev, Pavel and Mallet, William and Piizzi, Grazia and Wang, Peiyin and Zurini, Mauro and Rudewicz, Patrick (2019) Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization. ACS Medicinal Chemistry Letters. ISSN 1948-58751948-5875

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 study were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbonate, 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 non-cleavable linkers, and the resulting conjugates (ADC-4, ADC-11 and ADC-12) led to in-vivo efficacy in a HER-2 expressing (SK-OV-3ip) mouse xenograft model in a target-dependent manner.

Item Type: Article
Date Deposited: 21 Dec 2019 00:45
Last Modified: 21 Dec 2019 00:45
URI: https://oak.novartis.com/id/eprint/40986

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