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The biodistribution of therapeutic proteins: Mechanism, implications for pharmacokinetics, and methods of evaluation.
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2020-05-17 , DOI: 10.1016/j.pharmthera.2020.107574
Kip P Conner 1 , Siva Charan Devanaboyina 1 , Veena A Thomas 1 , Dan A Rock 1
Affiliation  

Therapeutic proteins (TPs) are a diverse drug class that include monoclonal antibodies (mAbs), recombinantly expressed enzymes, hormones and growth factors, cytokines (e.g. chemokines, interleukins, interferons), as well as a wide range of engineered fusion scaffolds containing IgG1 Fc domain for half-life extension. As the pharmaceutical industry advances more potent and selective protein-based medicines through discovery and into the clinical stages of development, it has become widely appreciated that a comprehensive understanding of the mechanisms of TP biodistribution can aid this endeavor. This review aims to highlight the literature that has advanced our understanding of the determinants of TP biodistribution. A particular emphasis is placed on the multi-faceted role of the neonatal Fc receptor (FcRn) in mAb and Fc-fusion protein disposition. In addition, characterization of the TP-target interaction at the cell-level is discussed as an essential strategy to establish pharmacokinetic-pharmacodynamic (PK/PD) relationships that may lead to more informed human dose projections during clinical development. Methods for incorporation of tissue and cell-level parameters defining these characteristics into higher-order mechanistic and semi-mechanistic PK models will also be presented.

中文翻译:

治疗性蛋白质的生物分布:作用机理,对药代动力学的影响和评估方法。

治疗性蛋白质(TPs)是一类多样化的药物,包括单克隆抗体(mAb),重组表达的酶,激素和生长因子,细胞因子(例如趋化因子,白介素,干扰素),以及各种包含IgG1 Fc的工程融合支架半衰期域。随着制药业通过发现并进入临床开发阶段而发展出更有效和更具选择性的蛋白质基药物,对TP生物分布机制的全面理解可以帮助实现这一目标,这已广为人知。这篇综述旨在突出那些已经使我们对TP生物分布决定因素有更深入了解的文献。特别强调的是新生儿Fc受体(FcRn)在mAb和Fc融合蛋白配置中的多方面作用。此外,在细胞水平上对TP-靶标相互作用的表征是建立药代动力学-药效学(PK / PD)关系的必要策略,在临床开发过程中可能导致更合理的人体剂量预测。还介绍了将定义这些特征的组织和细胞水平参数纳入高阶机械和半机械PK模型的方法。
更新日期:2020-05-17
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