Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies.
Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies.
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DOI：
10.1080/19420862.2021.1993769
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发表时间：
2021-01
期刊：
影响因子：
5.3
通讯作者：
Shah DK
中科院分区：
文献类型：
--
作者：
Liu S;Verma A;Kettenberger H;Richter WF;Shah DK
越来越多的证据支持分子电荷在抗体药代动力学(PK)中的重要作用，但对电荷对抗体系统和组织处置的影响的定量描述仍然缺乏。因此，我们系统地设计了曲妥珠单抗的互补决定区(CDR)，创建了一系列等电点(PI)范围为6.38.9，可变区(Fv)电荷范围为−8.9至+10.9(在pH 5.5时)的变体，并研究了这些分子的体外和体内处置。这些单抗(MAbs)在抗原阴性的细胞中表现出与细胞表面结合和细胞摄取增加的正电荷。在小鼠单次静脉给药后，观察到全身暴露与FV电荷之间呈钟形关系，延长的负电荷和正电荷贴片都导致更快的非特异性清除。全身PK实验显示，尽管大多数变异体在组织中的总体暴露非常相似，但mAbs的正电荷导致大多数组织的组织与血浆浓度比显著增加。在肝、脾、肾等血流良好的器官中，正电荷变异体表现出优越的蓄积。在脂肪、肌肉、皮肤和骨骼等具有连续毛细血管的组织中，血浆浓度控制着组织的暴露。给出的体外和体内处置数据有助于更好地了解电荷修饰对抗体PK的影响，并提示电荷的改变可能有助于改善某些组织中单抗的组织：血浆浓度比。本文提供的数据也为建立包含电荷变化的单抗的生理学药代动力学模型铺平了道路。
A growing body of evidence supports the important role of molecular charge on antibody pharmacokinetics (PK), yet a quantitative description of the effect of charge on systemic and tissue disposition of antibodies is still lacking. Consequently, we have systematically engineered complementarity-determining regions (CDRs) of trastuzumab to create a series of variants with an isoelectric point (pI) range of 6.3–8.9 and a variable region (Fv) charge range of −8.9 to +10.9 (at pH 5.5), and have investigated in vitro and in vivo disposition of these molecules. These monoclonal antibodies (mAbs) exhibited incrementally enhanced binding to cell surfaces and cellular uptake with increased positive charge in antigen-negative cells. After single intravenous dosing in mice, a bell-shaped relationship between systemic exposure and Fv charge was observed, with both extended negative and positive charge patches leading to more rapid nonspecific clearance. Whole-body PK experiments revealed that, although overall exposures of most variants in the tissues were very similar, positive charge of mAbs led to significantly enhanced tissue:plasma concentration ratios for most tissues. In well-perfused organs such as liver, spleen, and kidney, the positive charge variants show superior accumulation. In tissues with continuous capillaries such as fat, muscle, skin, and bone, plasma concentrations governed tissue exposures. The in vitro and in vivo disposition data presented here facilitate better understanding of the impact of charge modifications on antibody PK, and suggest that alteration in the charge may help to improve tissue:plasma concentration ratios for mAbs in certain tissues. The data presented here also paves the way for the development of physiologically based pharmacokinetic models of mAbs that incorporate charge variations.
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影响因子：
4.8
作者：
Claypool, SM;Dickinson, BL;Blumberg, RS
通讯作者：
Blumberg, RS
影响因子：
2.4
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影响因子：
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作者：
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通讯作者：
Blumberg, RS
影响因子：
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作者：
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通讯作者：
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