(Crown Bio) An Integrated DMPK and Bioanalytical Platform for Comprehensive Characterization of Antibody-Drug Conjugates

Abstract

Antibody-drug conjugates (ADCs) represent a transformative class of targeted oncology therapeutics, with their efficacy and safety profiles critically dependent on their pharmacokinetic (PK) behavior and biotransformation in vivo. However, their complex structure introduces significant challenges in characterization, necessitating a holistic DMPK strategy to understand their in vitro stability, in vivo PK and biodistribution, and biotransformation. The success of this strategy hinges on the precise quantification of key analytes, including total antibody (Tab), conjugated antibody (ADC), free payload, and the drug-to-antibody ratio (DAR), in diverse biological matrices. Here, we present a robust ADC DMPK evaluation platform, which combines integrated in vitro drug stability, payload release assessment, and in vivo PK/PD studies with a versatile bioanalytical platform, demonstrating its utility through a direct comparison of three clinically relevant ADCs with distinct designs: Trastuzumab Deruxtecan (T-DXd), Trastuzumab Emtansine (T-DM1) and Enfortumab Vedotin (EV). This comprehensive approach is designed to delineate in vivo PK behavior and biotransformation pathways, providing critical pharmacology and safety data to de-risk the translational path of ADC candidates from discovery through to preclinical stage.