A predictive model of therapeutic monoclonal antibody dynamics and regulation by the neonatal fc receptor (FcRn)

被引:113
作者
Ferl, GZ
Wu, AM
DiStefano, JJ
机构
[1] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Biomed Engn Interdepartmental Program, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, Biocybernet Lab, Los Angeles, CA 90095 USA
[5] Univ Calif Los Angeles, Sch Med, Dept Mol & Med Pharmacol, Crump Inst Mol Imaging, Los Angeles, CA 90024 USA
关键词
monoclonal Antibodies; neonatal Fc receptor; mathematical model; Animal Models; pharmacokinetics;
D O I
10.1007/s10439-005-7410-3
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
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.
引用
收藏
页码:1640 / 1652
页数:13
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