Application of FcRn binding assays to guide mAb development.
Application of FcRn binding assays to guide mAb development.
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DOI：
10.1124/dmd.114.059089
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发表时间：
2014-11-01
期刊：
影响因子：
--
通讯作者：
Wroblewski, Victor J
中科院分区：
文献类型：
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作者：
Datta-Mannan, Amita;Wroblewski, Victor J
单克隆抗体（mab）是一类重要的治疗方式。为了优化它们的药物特性，研究集中在通过调节它们与新生儿Fc受体（FcRn）的相互作用来改善单抗的药代动力学/药效学特征。在FcRn相互作用的背景下，研究了igg的化学和物理性质的影响。在这方面，已经开发了各种FcRn结合分析和工具，并用于表征与igg的相互作用。然而，体外igg的FcRn结合相互作用与体内单抗药代动力学之间的预测关系仍然难以捉摸。越来越多的研究表明，单克隆抗体的特性与其靶标的性质之间的相互作用可以影响其处置和消除。因此，越来越明显的是，随着FcRn的相互作用，在单抗开发和优化中应该考虑在单抗处置中活跃的非FcRn生物过程。在本文中，我们描述了单克隆抗体的药代动力学如何通过FcRn相互作用被调节，并提供了解释受体结合参数与抗体配置相关的其他机制的观点，以帮助指导单克隆抗体的开发。
Monoclonal antibodies (mAbs) represent an important class of therapeutic modalities. To optimize their pharmaceutical properties, studies have focused on improving mAb pharmacokinetic/pharmacodynamic profiles by modulating their interactions with the neonatal Fc receptor (FcRn). The influence of both the chemical and physical properties of IgGs has been examined in the context of FcRn interactions. In this regard, a variety of FcRn binding assays and tools have been developed and used to characterize the interaction with IgGs. However, a predictive relationship between the FcRn binding interaction of IgGs in vitro and their pharmacokinetics in vivo broadly across mAbs remains elusive. Many studies have increasingly suggested that the interplay between the characteristics of the mAb and the nature of its target can influence disposition and elimination. Thus, it is becoming increasingly evident that along with FcRn interactions, consideration of the non-FcRn-based biologic processes active in mAb disposition should be integrated into mAb development and optimization. Herein, we describe how the pharmacokinetics of mAbs can be modulated through FcRn interactions and provide perspectives on interpreting the receptor binding parameters in relation to other mechanisms involved in antibody disposition to aid in guiding mAb development.