Open AccessDiscovery of Potent and Selective Antibody–Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization
Author(s) -
Alexei S. Karpov,
CristiietoOberhuber,
Tinya J. Abrams,
Edwige Beng-Louka,
E Blanco,
Sylvie Chamoin,
Patrick Chêne,
Isabelle Dacquignies,
Dylan Daniel,
Michael P. Dillon,
Lionel Doumampouom-Metoul,
Nikolaos Drosos,
Pavel Fedoseev,
Markus Furegati,
Brian Granda,
Robert M. Grotzfeld,
Suzanna Clark,
Emilie Joly,
Darryl Jones,
Marion Lacaud-Baumlin,
Stephanie Lagasse-Guerro,
Edward Lorenzana,
William Mallet,
Piotr Martyniuk,
Andreas L. Marzinzik,
Yannick Mesrouze,
Sandro Nocito,
Yoko Oei,
Francesca Perruccio,
Grazia Piizzi,
Etienne Richard,
Patrick J. Rudewicz,
Patrick Schindler,
Mélanie Velay,
Kristine Venstrom,
Peiyin Wang,
Mauro Zurini,
Marc Lafrance
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00468
Subject(s) - in vivo , linker , conjugate , antibody drug conjugate , chemistry , payload (computing) , antibody , pharmacology , cancer research , monoclonal antibody , medicine , biology , immunology , computer science , mathematical analysis , computer network , microbiology and biotechnology , mathematics , network packet , operating system
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.