A strategy for risk mitigation of antibodies with fast clearance
A strategy for risk mitigation of antibodies with fast clearance
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DOI：
10.4161/mabs.22189
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发表时间：
2012-11-01
期刊：
影响因子：
5.3
通讯作者：
Kelley, Robert F.
中科院分区：
文献类型：
--
作者：
Hoetzel, Isidro;Theil, Frank-Peter;Kelley, Robert F.
大多数人类治疗性抗体候选物显示出适合临床使用的药代动力学特性，但有时观察到出乎意料的快速抗体清除可能限制临床应用。在食蟹猴中收集的52种抗体的药代动力学数据显示，与靶标无关的清除率分布广泛（2.4-61.3 mL/天/kg），其中15只（29%）的清除率为10 mL/天/kg。与循环FcRn受体相互作用的改变并不能解释观察到的抗体比预期更快的清除；脱靶结合被认为是快速清除的原因。我们开发了一种基于ELISA检测非特异性结合杆状病毒颗粒的检测方法，可以识别具有快速清除风险增加的抗体。该试验可用于先导物生成或优化过程中，以识别在人类和食蟹猴中具有快速清除风险的抗体，从而增加获得合适候选药物的可能性。
A majority of human therapeutic antibody candidates show pharmacokinetic properties suitable for clinical use, but an unexpectedly fast antibody clearance is sometimes observed that may limit the clinical utility. Pharmacokinetic data in cynomolgus monkeys collected for a panel of 52 antibodies showed broad distribution of target-independent clearance values (2.4-61.3 mL/day/kg), with 15 (29%) having clearance > 10 mL/day/kg. Alteration in the interaction with the recycling FcRn receptor did not account for the faster than expected clearance observed for the antibodies; off-target binding was presumed to account for the fast clearance. We developed an assay based on ELISA detection of non-specific binding to baculovirus particles that can identify antibodies having increased risk for fast clearance. This assay can be used during lead generation or optimization to identify antibodies with increased risk of having fast clearance in both humans and cynomolgus monkeys, and thus increase the likelihood of obtaining a suitable drug candidate.