Design, Synthesis, and In Vitro and In Vivo Evaluation of Cereblon Binding Bruton’s Tyrosine Kinase (BTK) Degrader CD79b Targeted Antibody–Drug Conjugates

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 more sustained in vivo degradation than iv administered 1 with markedly reduced systemic exposure of the payload.