title: Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling.
abstract: Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity.
authors.affiliation: Pharmacology & Drug Development Group, Department of Oncology, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK. bfk22@cam.ac.uk
authors.forename: Ben-Fillippo
authors.initials: BF
authors.lastname: Krippendorff
authors.forename: Diego A
authors.initials: DA
authors.lastname: Oyarzún
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Huisinga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D005544:Forecasting; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000502:physiology*; D008252:Macaca fascicularis; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; C546618:zalutumumab