Correlations between pharmacokinetics of IgG antibodies in primates vs. FcRn-transgenic mice reveal a rodent model with predictive capabilities
Correlations between pharmacokinetics of IgG antibodies in primates vs. FcRn-transgenic mice reveal a rodent model with predictive capabilities
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DOI：
10.4161/mabs.23836
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发表时间：
2013-05-01
期刊：
影响因子：
5.3
通讯作者：
Scallon, Bernard J.
中科院分区：
文献类型：
--
作者：
Tam, Susan H.;McCarthy, Stephen G.;Scallon, Bernard J.
表达人新生Fc受体（FcRn）而非小鼠FcRn的转基因小鼠可用于IgG抗体药代动力学（PK）研究。考虑到对啮齿动物模型的兴趣，该模型可以提供猴子和人类抗体PK的可靠预测，我们开始测试这些小鼠中IgG抗体的PK是否与灵长类动物中相同抗体的PK相关。我们首先使用单一的研究抗体来研究：(1)不同的转基因小鼠系在FcRn转基因表达上的差异；(2)纯合子与半合子FcRn转基因小鼠；(3)共注射高剂量人静脉免疫球蛋白（IVIG）的存在与不存在；(4)共注射高剂量人血清白蛋白（HSA）的存在与不存在。这些研究结果表明，未使用IVIG或HSA处理的半合子Tg32小鼠（Tg32 hemi）有可能作为人类PK的预测模型。然后在这些条件下用一组测试抗体进行小鼠PK研究，这些抗体在小鼠和灵长类动物中的PK不受靶标结合的显著影响，并且猴子或人类的PK数据很容易获得。研究结果显示，在小鼠中观察到的终末半衰期或清除率值与在人类中报告的相应值之间存在显著相关性。小鼠和猴子之间的清除率也有显著的关系。这些相关性表明，Tg32半小鼠模型既方便又经济，可以在预测灵长类动物抗体半衰期和清除率方面提供价值。
Transgenic mice expressing human neonatal Fc receptor (FcRn) instead of mouse FcRn are available for IgG antibody pharmacokinetic (PK) studies. Given the interest in a rodent model that offers reliable predictions of antibody PK in monkeys and humans, we set out to test whether the PK of IgG antibodies in such mice correlated with the PK of the same antibodies in primates. We began by using a single research antibody to study the influence of: (1) different transgenic mouse lines that differ in FcRn transgene expression; (2) homozygous vs. hemizygous FcRn transgenic mice; (3) the presence vs. absence of coinjected high-dose human intravenous immunoglobulin (IVIG), and (4) the presence vs. absence of coinjected high-dose human serum albumin (HSA). Results of those studies suggested that use of hemizygous Tg32 mice (Tg32 hemi) not treated with IVIG or HSA offered potential as a predictive model for PK in humans. Mouse PK studies were then done under those conditions with a panel of test antibodies whose PK in mice and primates is not significantly affected by target binding, and for which monkey or human PK data were readily available. Results from the studies revealed significant correlations between terminal half-life or clearance values observed in the mice and the corresponding values reported in humans. A significant relationship in clearance values between mice and monkeys was also observed. These correlations suggest that the Tg32 hemi mouse model, which is both convenient and cost-effective, can offer value in predicting antibody half-life and clearance in primates.