Karpov, Alexei, Nieto-Oberhuber, Cristina, Grotzfeld, Robert, Abrams, Tinya, Beng-Louka, Edwige, Chamoin, Sylvie, Chene, Patrick, Clark, Suzy, Dacquignies, Isabelle, Doumampouom Metoul, Lionel, Furegati, Markus, Granda, Brian, Joly, Emilie, Jones, Darryl, Lacaud-Baumlin, Marion, Guerro-Lagasse, Stephanie, Lorenzana, Edward, Martyniuk, Piotr, Marzinzik, Andreas, Mesrouze, Yannick, Nocito, Sandro, Oei, Yoko, Perruccio, Francesca, Richard, Etienne, Schindler, Patrick, Velay, Melanie, Venstrom, Kristine, Lafrance, Marc, Blanco, Enrique , Daniel, Dylan, Dillon, Michael, Drosos, Nikolaos, Fedoseev, Pavel, Mallet, William , Piizzi, Grazia, Wang, Peiyin , 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