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

  • ACS Med Chem Lett. 2019 Dec 3;10(12):1674-1679. doi: 10.1021/acsmedchemlett.9b00468.
Alexei S Karpov  1 Cristina M Nieto-Oberhuber  1 Tinya Abrams  2 Edwige Beng-Louka  1 Enrique Blanco  1 Sylvie Chamoin  1 Patrick Chene  1 Isabelle Dacquignies  1 Dylan Daniel  3 Michael P Dillon  2 Lionel Doumampouom-Metoul  1 Nikolaos Drosos  1  2  3 Pavel Fedoseev  1 Markus Furegati  1 Brian Granda  2 Robert M Grotzfeld  1 Suzanna Hess Clark  2 Emilie Joly  1 Darryl Jones  1 Marion Lacaud-Baumlin  1 Stephanie Lagasse-Guerro  1 Edward G Lorenzana  3 William Mallet  3 Piotr Martyniuk  1 Andreas L Marzinzik  1 Yannick Mesrouze  1 Sandro Nocito  1 Yoko Oei  3 Francesca Perruccio  1 Grazia Piizzi  1 Etienne Richard  1 Patrick J Rudewicz  3 Patrick Schindler  1 Mélanie Velay  1 Kristine Venstrom  3 Peiyin Wang  3 Mauro Zurini  1 Marc Lafrance  1  2
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Fabrikstrasse 2, CH-4056 Basel, Switzerland.
  • 2. Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 3. Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
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.

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