Development and Application of a Single Cell-Level PK-PD Model for ADCs

Development of antibody–drug conjugate (ADC) molecules is challenging, since it requires simultaneous optimization of three different ADC-related components (i.e., antibody, linker, and payload). Pharmacokinetic and pharmacodynamic (PK-PD) modeling and simulation is a powerful tool that can help with this process. It provides a rigorous understanding of how each ADC-related component impacts whole-body disposition and pharmacology of ADCs, and facilitates decision making in drug development. Among many PK-PD models of various anatomical levels available for ADCs, a cellular PK-PD model is the most mechanistic and conserved across different drug development stages. In this chapter, we present one such cell-level PK-PD model that integrates system-specific and ADC-specific parameters to describe intracellular processing of ADCs and their efficacy. We highlight how the model can be informed by cellular PK data, how it can be evolved to evaluate phenomena such as the bystander effect, and how it can be nested in a high-level systems PK-PD platform to achieve preclinical-to-clinical translation of ADCs. The cellular PK-PD model presented here provides a flexible quantitative framework, which can be used to triage ADC molecules at the development stage and evaluate different strategies to improve ADC therapy in the clinic.