A mechanistic pharmacokinetic-pharmacodynamic model for degrader-antibody conjugates.

Degrader-antibody conjugates (DACs) represent an emerging class of innovative therapeutics that combine the unique delivery capabilities of antibody-drug conjugates (ADCs) with the catalytic targeted protein degradation capabilities of proteolysis-targeting chimeras (PROTACs). To support the rational design and optimization of this new therapeutic modality, a pharmacokinetic-pharmacodynamic (PK-PD) model framework for DACs was developed to integrate the mechanisms of targeted protein degradation and antibody-mediated drug delivery. The model was calibrated with previously published in vitro and in vivo data for DACs and their PROTAC payloads. The PK module for antibody-mediated PROTAC delivery was linked to a PD module capturing ternary complex formation and protein degradation by the released PROTAC. Downstream pharmacological activity, such as inhibition of cell proliferation for oncology applications, was driven by the changes in target protein levels. The model framework captured the PK and PD of unconjugated and antibody-conjugated PROTACs, linking intracellular PROTAC concentration to protein degradation, in vitro cell proliferation, and in vivo tumor growth inhibition. Model simulations enabled exploration of parameters influencing DAC efficacy, including expression level and internalization efficiency of the surface antigen for antibody targeting, the composition and stability of the antibody-PROTAC linker, and PROTAC payload potency and permeability. The model framework establishes design constraints for antibody, linker, and payload selection and optimization, providing practical insights that can improve the probability of success for novel DAC therapeutics.