Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys
Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys
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DOI：
10.4161/mabs.4.2.19364
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发表时间：
2012-03-01
期刊：
影响因子：
5.3
通讯作者：
Wroblewski, Victor J.
中科院分区：
文献类型：
--
作者：
Datta-Mannan, Amita;Witcher, Derrick R.;Wroblewski, Victor J.
设计与新生儿Fc受体（FcRn）结合增强的单克隆抗体（mAb）是一种可以延长其体内半衰期并减缓其全身清除的策略。已发表的报告主要描述了静脉给药后mAb的药代动力学特征。最近，在小鼠中的研究表明FcRn也可能在影响mAb的皮下生物利用度方面发挥作用。在本文中，我们检查了用T250 Q/M428 L Fc突变工程化的五种mAb与食蟹猴中的野生型对应物相比是否具有改善的皮下生物利用度，所述突变改善了它们的FcRn相互作用，并且随后改善了它们在静脉内施用后的体内药代动力学。与静脉内给药结果相似，我们的变体mAb在皮下注射后的药代动力学曲线显示半衰期或清除率改善。相比之下，未观察到对皮下生物利用度的明显影响。我们预计，虽然FcRn可能在确定mAb皮下生物利用度方面发挥作用，但多种生物制药和生理因素可能会影响旨在靶向该途径以改善生物利用度的工程策略的成功。
Engineering monoclonal antibodies (mAbs) with improved binding to the neonatal Fc receptor (FcRn) is a strategy that can extend their in vivo half-life and slow their systemic clearance. Published reports have predominantly characterized the pharmacokinetics of mAbs after intravenous administration. Recently, studies in mice suggest FcRn may also play a role in affecting the subcutaneous bioavailability of mAbs. Herein, we examined whether five mAbs engineered with the T250Q/M428L Fc mutations that improved their FcRn interactions, and subsequently their in vivo pharmacokinetics after intravenous administration, had improved subcutaneous bioavailability compared with their wild-type counterparts in cynomolgus monkeys. Similar to the intravenous administration findings, the pharmacokinetic profiles of our variant mAbs after subcutaneous injection showed improved half-life or clearance. In contrast, a clear effect was not observed on the subcutaneous bioavailability. We expect that while FcRn may play a role in determining mAb subcutaneous bioavailability, multiple biopharmaceutical and physiological factors are likely to influence the success of engineering strategies aimed at targeting this pathway for improving bioavailability.