Application of human FcRn transgenic mice as a pharmacokinetic screening tool of monoclonal antibody
Application of human FcRn transgenic mice as a pharmacokinetic screening tool of monoclonal antibody
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DOI：
10.3109/00498254.2014.941963
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发表时间：
2014-12-01
期刊：
影响因子：
1.8
通讯作者：
Ishigai, Masaki
中科院分区：
文献类型：
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作者：
Haraya, Kenta;Tachibana, Tatsuhiko;Ishigai, Masaki
1.对于药物发现，有用的筛选工具对于选择上级候选物是必不可少的。在此，我们评估了表达人新生儿Fc受体（FcRn）（hFcRn Tgm）的转基因小鼠作为治疗性单克隆抗体（mAb）和Fc融合蛋白的药代动力学筛选工具的适用性，该工具克服了FcRn结合的物种差异.将市售的11种mAb和2种Fc融合蛋白静脉内施用至hFcRn Tgm和WT小鼠。将hFcRn Tgm和WT小鼠中的半衰期与从文献中获得的人中的半衰期进行比较。还通过非线性药代动力学分析计算了人和猴中的线性半衰期。为了比较，还评估了猴和人之间半衰期的相关性。静脉内给药后，mAb和Fc融合蛋白的半衰期在hFcRn Tgm中为1.1至13.2天，在WT小鼠中为1.2至30.3天。与WT小鼠和猴相比，人中的半衰期与hFcRn Tgm中的半衰期更密切相关。我们的研究结果表明，hFcRn Tgm是一个有价值的和有用的工具，在临床前阶段的单克隆抗体和Fc融合蛋白的药代动力学筛选。此外，我们相信hFcRn Tgm广泛适用于基于mAb的治疗剂的临床前药代动力学筛选。
1. For drug discovery, useful screening tools are essential to select superior candidates. Here, we evaluated the applicability of transgenic mice expressing human neonatal Fc receptor (FcRn) (hFcRn Tgm) as a pharmacokinetic screening tool of therapeutic monoclonal antibodies (mAbs) and Fc-fusion proteins that overcomes the species difference in FcRn binding.2. Marketed 11 mAbs and 2 Fc-fusion proteins were intravenously administered to hFcRn Tgm and WT mice. The half-lives in hFcRn Tgm and WT mice were compared with those in human obtained from literature. The linear half-lives in human and monkey were also calculated by nonlinear pharmacokinetic analysis. For comparison, correlations of half-lives between monkey and human were also evaluated.3. The half-lives of mAbs and Fc-fusion proteins after intravenous administration ranged from 1.1 to 13.2 days in hFcRn Tgm and from 1.2 to 30.3 days in WT mice. The half-lives in human correlated more closely with those in hFcRn Tgm than in WT mice and monkey.4. Our results suggest that hFcRn Tgm are a valuable and useful tool for pharmacokinetic screening of mAbs and Fc-fusion proteins in the preclinical stage. Furthermore, we believe that hFcRn Tgm are broadly applicable to preclinical pharmacokinetic screening of mAbs-based therapeutics.