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

• DOI: 10.1021/acs.bioconjchem.3c00535
• Publication Date: 2024-01-24T16:11:05Z
• Authors: Alan Zhang; Katherine Seiss; Laurent Laborde; Sebastian Palacio...; 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. Hollin...; Joseph A. D’Alessio; Stephane Ferretti; Matthew T. Burger
• Keywords: Antibody-drug conjugate; Linker; Conjugate; Cereblon; Hapten

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