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A Predictive Model of Therapeutic Monoclonal Antibody Dynamics and Regulation by the Neonatal Fc Receptor (FcRn)

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An Erratum to this article was published on 05 August 2011

Abstract

We constructed a novel physiologically-based pharmacokinetic (PBPK) model for predicting interactions between the neonatal Fc receptor (FcRn) and anti-carcinoembryonic antigen (CEA) monoclonal antibodies (mAbs) with varying affinity for FcRn. Our new model, an integration and extension of several previously published models, includes aspects of mAb-FcRn dynamics within intracellular compartments not represented in previous PBPK models. We added mechanistic structure that details internalization of class G immunoglobulins by endothelial cells, subsequent FcRn binding, recycling into plasma of FcRn-bound IgG and degradation of free endosomal IgG. Degradation in liver is explicitly represented along with the FcRn submodel in skin and muscle. A variable tumor mass submodel is also included, used to estimate the growth of an avascular, necrotic tumor core, providing a more realistic picture of mAb uptake by tumor. We fitted the new multiscale model to published anti-CEA mAb biodistribution data, i.e. concentration-time profiles in tumor and various healthy tissues in mice, providing new estimates of mAb-FcRn related kinetic parameters. The model was further validated by successful prediction of F(ab′)2 mAb fragment biodistribution, providing additional evidence of its potential value in optimizing intact mAb and mAb fragment dosing for clinical imaging and immunotherapy applications.

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Authors and Affiliations

  1. Biocybernetics Laboratory, Departments of Computer Science and Medicine and Biomedical Engineering Interdepartmental Program, University of California, Los Angeles

    Gregory Z. Ferl & Joseph J. DiStefano III

  2. Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles

    Anna M. Wu

  3. Department of Computer Science, 4711 Boelter Hall, Los Angeles, CA, 90095-1596

    Joseph J. DiStefano III

Authors
  1. Gregory Z. Ferl
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Correspondence to Joseph J. DiStefano III.

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An erratum to this article is available at http://dx.doi.org/10.1007/s10439-011-0373-7.

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Ferl, G.Z., Wu, A.M. & DiStefano, J.J. A Predictive Model of Therapeutic Monoclonal Antibody Dynamics and Regulation by the Neonatal Fc Receptor (FcRn). Ann Biomed Eng 33, 1640–1652 (2005). https://doi.org/10.1007/s10439-005-7410-3

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  • DOI: https://doi.org/10.1007/s10439-005-7410-3

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