A Physiologically-Based Pharmacokinetic Model for the Prediction of 'Half-Life Extension' and 'Catch and Release' Monoclonal Antibody Pharmacokinetics.

Monoclonal antibodies (mAbs) can be engineered to have 'extended half-life' and 'catch and release' properties to improve target coverage. We have developed a mAb physiologically based pharmacokinetic (PBPK) model that describes intracellular trafficking, neonatal Fc receptor (FcRn) recycling and non-specific clearance of mAbs. We extended this model to capture target binding as a function of target affinity, expression and turnover. For mAbs engineered to have an 'extended half-life', the model was able to accurately predict the terminal half-life (82% within 2-fold error of the observed value) in the human FcRn transgenic (Tg32) homozygous mouse and human. The model also accurately captures the trend in PK and target coverage data for a set of mAbs with differing 'catch and release' properties in Tg32 mouse. The mechanistic nature of this model allows us to explore different engineering techniques early in drug discovery, potentially expanding the number of 'druggable' targets.