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Design, Synthesis, In Vitro and In Vivo Evaluation of Cereblon Binding Bruton’s Tyrosine Kinase (BTK) Degrader CD79 targeted Antibody-Drug Conjugates

Zhang, Alan, Seiss, Katherine, Laborde, Laurent, Guthy, Daniel Alexander, Lanter, Mylene, Lorber, Julien, Vulpetti, Anna, Hebach, Christina, Zoller, Thomas, Tschantz, Bill, Hollingworth, Greg, D'Alessio, Tony, Ferretti, Stephane Raymond, Karpov, Alexei and Burger, Matthew (2024) Design, Synthesis, In Vitro and In Vivo Evaluation of Cereblon Binding Bruton’s Tyrosine Kinase (BTK) Degrader CD79 targeted Antibody-Drug Conjugates. Bioconjugate chemistry. ISSN 1520-4812; 1043-1802

Abstract

Antibody-drug conjugates (ADCs) are an established modality which allows for targeted delivery of a potent molecule, or payload, to a desired site of action. ADCs, wherein the payload is a targeted protein degrader is an emerging area in the field. Herein we describe our efforts of delivering a Bruton’s tyrosine kinase (BTK) bifunctional degrader 1 via a CD79b mAb where the degrader is linked at the ligase binding portion of the payload via a cleavable linker to the mAb. The resulting CD79b ADCs, 3 and 4, exhibit in vitro degradation and cytotoxicity comparable to 1 and ADC 3 can achieve greater in vivo degradation than 1 with markedly reduced systemic exposure of the payload.

Item Type: Article
Keywords: antibody drug conjugates, bifunctional degrader, antibody degrader conjugates
Date Deposited: 08 Feb 2024 00:45
Last Modified: 08 Feb 2024 00:45
URI: https://oak.novartis.com/id/eprint/52293

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