Toward in vitro-to-in vivo translation of monoclonal antibody pharmacokinetics: Application of a neonatal Fc receptor-mediated transcytosis assay to understand the interplaying clearance mechanisms
Toward in vitro-to-in vivo translation of monoclonal antibody pharmacokinetics: Application of a neonatal Fc receptor-mediated transcytosis assay to understand the interplaying clearance mechanisms
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DOI：
10.1080/19420862.2017.1320008
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发表时间：
2017-01-01
期刊：
影响因子：
5.3
通讯作者：
Simon, Silke
中科院分区：
文献类型：
--
作者：
Jaramillo, Claudia A. Castro;Belli, Sara;Simon, Silke
单克隆抗体（mAb）是一种快速增长的药物类别，人们已经做出了很大努力来优化某些分子特征，以实现所需的药代动力学（PK）特性。一种方法是通过引入特定的氨基酸序列突变来设计mAb与新生儿Fc受体（FcRn）的相互作用，并通过体内研究评估它们对PK特征的影响。事实上，FcRn保护mAb免于细胞内降解，从而延长抗体在血浆中的循环时间并调节其全身清除。为了实现更有效和更集中的mAb优化，体外输入有助于识别和定量预测驱动体内非靶标介导的mAb清除的不同过程的贡献并支持翻译PK建模活动是必不可少的。为此，我们评价了体外细胞FcRn介导的转胞吞试验的适用性和体内相关性，以解释25种mAb在大鼠或猴中的PK行为。该试验能够捕获IgG-FcRn相互作用的种属特异性差异，并根据其体内清除率对Fc突变体进行总体正确排序。然而，它不能解释所有检测IgG的PK行为，表明mAb体内处置是除FcRn相互作用之外的其他过程的复杂相互作用。总体而言，认为转胞吞测定适合在广泛的体内测试之前对mAb候选物的FcRn介导的清除组分进行排名，并且代表了基于体外数据的多因素体内清除预测方法的第一步。
Monoclonal antibodies (mAbs) are a rapidly growing drug class for which great efforts have been made to optimize certain molecular features to achieve the desired pharmacokinetic (PK) properties. One approach is to engineer the interactions of the mAb with the neonatal Fc receptor (FcRn) by introducing specific amino acid sequence mutations, and to assess their effect on the PK profile with in vivo studies. Indeed, FcRn protects mAbs from intracellular degradation, thereby prolongs antibody circulation time in plasma and modulates its systemic clearance. To allow more efficient and focused mAb optimization, in vitro input that helps to identify and quantitatively predict the contribution of different processes driving non-target mediated mAb clearance in vivo and supporting translational PK modeling activities is essential. With this aim, we evaluated the applicability and in vivo-relevance of an in vitro cellular FcRn-mediated transcytosis assay to explain the PK behavior of 25 mAbs in rat or monkey. The assay was able to capture species-specific differences in IgG-FcRn interactions and overall correctly ranked Fc mutants according to their in vivo clearance. However, it could not explain the PK behavior of all tested IgGs, indicating that mAb disposition in vivo is a complex interplay of additional processes besides the FcRn interaction. Overall, the transcytosis assay was considered suitable to rank mAb candidates for their FcRn-mediated clearance component before extensive in vivo testing, and represents a first step toward a multi-factorial in vivo clearance prediction approach based on in vitro data.