BIODISTRIBUTION OF MONOCLONAL-ANTIBODIES - SCALE-UP FROM MOUSE TO HUMAN USING A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL

The efficacy of a novel diagnostic or therapeutic agent depends on its selective localization in a target tissue, Biodistribution studies ar e expensive and difficult to carry out in humans, but such data can be obtained easily in rodents. We have developed a physiologically based pharmacokinetic model for scaling up data from mice to humans, the fi rst such model for genetically engineered macromolecules that bind to their targets in vivo, such as mAbs, The mathematical model uses physi ological parameters including organ volumes, blood flow rates, and vas cular permeabilities; the compartments (organs) are connected anatomic ally, This allows the use of scale-up techniques to predict antibody d istribution in humans. The model was tested with data obtained in huma n patients for the biodistribution of a mAb against carcinoembryonic a ntigen. The model was further tested for a two-step protocol: bifuncti onal antibodies and radiolabeled hapten, which compared favorably with data in both mice and humans. The model was useful for optimization o f treatment parameters, such as dose and time interval of injections, binding affinities, and choice of molecular carrier, This framework ma y be applicable to other genetically engineered molecules (e.g., growt h factors, antisense oligonucleotides, and gene-carrying vectors).