Design,
Synthesis, and In Vitro and In Vivo Evaluation
of Cereblon Binding Bruton’s Tyrosine Kinase (BTK) Degrader
CD79b Targeted Antibody–Drug Conjugates
posted on 2024-01-24, 16:34authored byAlan Zhang, Katherine Seiss, Laurent Laborde, Sebastian Palacio-Ramirez, Daniel Guthy, Mylene Lanter, Julien Lorber, Anna Vulpetti, Luca Arista, Thomas Zoller, Thomas Radimerski, Claudio Thoma, Christina Hebach, William R. Tschantz, Alexei Karpov, Gregory J. Hollingworth, Joseph A. D’Alessio, Stephane Ferretti, Matthew T. Burger
Antibody–drug conjugates (ADCs) are an established
modality
that allow for targeted delivery of a potent molecule, or payload,
to a desired site of action. ADCs, wherein the payload is a targeted
protein degrader, are 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 (monoclonal antibody)
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 with that of 1, and ADC 3 can
achieve more sustained in vivo degradation than intravenously administered 1 with markedly reduced systemic exposure of the payload.