Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys
Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys
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DOI：
10.1080/19420862.2016.1178435
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发表时间：
2016-01-01
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;Croy, Johnny E.;Wroblewski, Victor J.
双特异性抗体(BsAbs)可以影响多种疾病途径，因此这些类型的构建物有可能为提高复杂疾病适应症的疗效提供有前途的方法。影响单抗药代动力学的特异性和非特异性清除机制/生物学可能与BsAbs的处置有关。尽管有这些相似之处，但关于影响BsAbs生物分布和药代动力学的体内生物学研究很少。本研究评价了两种免疫球蛋白融合的BsAb在食蟹猴体内的分布情况，这两种抗体被认为是免疫球蛋白Ig G-ECD(胞外区)和Ig G-scFv(单链抗体)。这些BsAb分子在体内表现出较差的药代动力学特性，包括快速清除(>；0.5ml/hr/kg)和与其对应的单抗相比半衰期较短。目前的工作评估了体内导致这些BsAb结构异常清除的因素。结果表明，BsAbs的快速清除不是由于靶向结合、新生儿Fc受体(FcRN)相互作用减少或分子/生化特性差所致。对构建体细胞分布的评估表明，主要的清除机制与与肝窦内皮细胞(LSECs)和肝巨噬细胞的结合/结合有关。这些研究中所描述的LSECs在促进Ig G-ECD和Ig G-scFv BsAb结构的清除中的作用与氯屈膦介导的巨噬细胞耗竭对这两个结构在食蟹猴体内的药代动力学的最小影响是一致的。本报告的发现是一个重要的证明，一些Ig G-ECD和Ig G-scFv BsAb分子的清除机制的阐明可能是独特和复杂的，由于这些更复杂的mAb样结构的增殖，可能需要更多的关注。
Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgG-scFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures.