2. Academic Validation
  3. Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization

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

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.
PMID: 31857845 DOI: 10.1021/acsmedchemlett.9b00468
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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