Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

摘要: Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later development processes, however, rely on pharmacokinetic compartment while cell-level dynamics are typically neglected. We here present a systematic approach to integrate and models. Incorporating target into is especially useful therapeutic antibodies because their effect pharmacokinetics inherently interdependent. The illustrated by analysing F(ab)-mediated inhibitory targeting epidermal growth factor receptor. build multi-level model anti-EGFR combining systems biology with in vitro determined parameters based vivo data. Using this model, we investigated silico impact biochemical properties effect. suggests that saturates increasing drug-receptor affinity, thereby limiting antibody affinity improving This indicates observed differences effects high market clinical may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity.