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.
- 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.
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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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer
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Research Areas: Cancer
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target: ADC PayloadsResearch Areas: Cancer
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Research Areas: Cancer