Alan 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...
January 24, 2024: Bioconjugate Chemistry