A predictive model of therapeutic monoclonal antibody dynamics and regulation by the neonatal fc receptor (FcRn)
A predictive model of therapeutic monoclonal antibody dynamics and regulation by the neonatal fc receptor (FcRn)
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DOI：
10.1007/s10439-005-7410-3
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发表时间：
2005-11-01
影响因子：
3.8
通讯作者：
DiStefano, JJ
中科院分区：
文献类型：
--
作者：
Ferl, GZ;Wu, AM;DiStefano, JJ
我们构建了一种新的基于生理学的药代动力学（PBPK）模型，用于预测新生儿Fc受体（FcRn）和具有不同FcRn亲和力的抗癌胚抗原（CEA）单克隆抗体（mAb）之间的相互作用。我们的新模型，集成和扩展的几个以前发表的模型，包括方面的单克隆抗体-FcRn的动态细胞内室不代表在以前的PBPK模型。我们添加了详细描述G类免疫球蛋白被内皮细胞内化、随后的FcRn结合、FcRn结合IgG再循环进入血浆以及游离内体IgG降解的机制结构。肝脏中的降解与皮肤和肌肉中的FcRn子模型一起明确表示为沿着。还包括可变肿瘤质量子模型，用于估计无血管坏死肿瘤核心的生长，提供肿瘤mAb摄取的更真实图像。我们将新的多尺度模型拟合到已发表的抗CEA mAb生物分布数据，即小鼠肿瘤和各种健康组织中的浓度-时间曲线，提供了mAb-FcRn相关动力学参数的新估计。通过成功预测F（ab '）（2）mAb片段生物分布进一步验证了该模型，提供了其在优化完整mAb和mAb片段给药用于临床成像和免疫治疗应用中的潜在价值的额外证据。
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.