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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