Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies
Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies
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DOI：
10.1080/19420862.2016.1193660
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发表时间：
2016-01-01
期刊：
影响因子：
5.3
通讯作者：
O'Hara, Denise M.
中科院分区：
文献类型：
--
作者：
Avery, Lindsay B.;Wang, Mengmeng;O'Hara, Denise M.
治疗性抗体作为一种新兴的药物类别继续发展，需要临床前工具来更好地预测体内特征。表达人新生儿Fc受体（hFcRn）的转基因小鼠具有作为临床前药代动力学（PK）模型来预测单克隆抗体（mAb）的人PK的潜力。使用一组具有广泛PK范围的27种mAb，我们试图表征和建立该临床前动物模型的实用性，并为其在mAb药物开发中的应用提供指导。将这组mAb以单次静脉内剂量给予半合子和纯合子hFcRn转基因小鼠（Tg 32），并推导PK参数。通过液相色谱-高分辨率串联质谱法在Tg 32纯合子小鼠与半合子小鼠中证实了更高的hFcRn蛋白组织表达。使用非房室分析计算清除率（CL），并评估与野生型小鼠、非人灵长类动物（NHP）和人的历史数据的相关性。结果显示，对于该数据集，hFcRn Tg 32纯合小鼠中的mAb CL与人的相关性（r（2）= 0.83，r = 0.91，p < 0.01）优于NHP（r（2）= 0.67，r = 0.82，p < 0.01）。应用简单的异速生长标度，使用经验得出的最佳拟合指数0.93，能够预测Tg 32纯合小鼠的人CL，100%检测的mAb的误差在2倍以内。在发现和临床前药物开发中实施Tg 32纯合小鼠模型以预测人CL可能导致PK研究中使用猴的总体减少，增强先导分子的早期选择，并最终缩短候选药物到达临床的时间。
Therapeutic antibodies continue to develop as an emerging drug class, with a need for preclinical tools to better predict in vivo characteristics. Transgenic mice expressing human neonatal Fc receptor (hFcRn) have potential as a preclinical pharmacokinetic (PK) model to project human PK of monoclonal antibodies (mAbs). Using a panel of 27 mAbs with a broad PK range, we sought to characterize and establish utility of this preclinical animal model and provide guidance for its application in drug development of mAbs. This set of mAbs was administered to both hemizygous and homozygous hFcRn transgenic mice (Tg32) at a single intravenous dose, and PK parameters were derived. Higher hFcRn protein tissue expression was confirmed by liquid chromatography-high resolution tandem mass spectrometry in Tg32 homozygous versus hemizygous mice. Clearance (CL) was calculated using non-compartmental analysis and correlations were assessed to historical data in wild-type mouse, non-human primate (NHP), and human. Results show that mAb CL in hFcRn Tg32 homozygous mouse correlate with human (r(2) = 0.83, r = 0.91, p < 0.01) better than NHP (r(2) = 0.67, r = 0.82, p < 0.01) for this dataset. Applying simple allometric scaling using an empirically derived best-fit exponent of 0.93 enabled the prediction of human CL from the Tg32 homozygous mouse within 2-fold error for 100% of mAbs tested. Implementing the Tg32 homozygous mouse model in discovery and preclinical drug development to predict human CL may result in an overall decreased usage of monkeys for PK studies, enhancement of the early selection of lead molecules, and ultimately a decrease in the time for a drug candidate to reach the clinic.