Reducing the antigen-independent toxicity of antibody-drug conjugates by minimizing their non-specific clearance through PEGylation
Reducing the antigen-independent toxicity of antibody-drug conjugates by minimizing their non-specific clearance through PEGylation
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DOI：
10.1016/j.taap.2020.114932
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发表时间：
2020-04-01
影响因子：
3.8
通讯作者：
Lyon, Robert P.
中科院分区：
文献类型：
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作者：
Simmons, Jessica K.;Burke, Patrick J.;Lyon, Robert P.
最近，我们描述了一系列非靶向单甲基阿里他汀 E (MMAE) 抗体药物偶联物 (ADC)，其药代动力学可以通过将多达 12 个单位的短聚乙二醇 (PEG) 部分掺入药物连接体中来调整，从而使 ADC 表面更加亲水。这项工作表明，在小鼠模型中，亲水性更强的 ADC 同时更有效且耐受性更好，表明通过该策略可以改善治疗指数。在这里，我们描述了 Sprague-Dawley 大鼠静脉给药后的生物分布和毒理学评估，旨在阐明这些生物学结果与非靶向 ADC 的潜在理化特性之间的关系。给予非聚乙二醇化 ADC 表现出快速的非特异性细胞摄取，导致 ADC 分解代谢和细胞毒性有效负载的快速释放，并在第一天内达到峰值血浆和组织浓度。引入四个、八个或十二个单元的 PEG 链会导致所有组织中的吸收速度越来越慢，并且峰值有效负载浓度降低。这些具有最小非特异性摄取的 ADC 还表现出显着较低的血液学毒性，骨髓的组织学耗竭减少，外周血细胞计数（中性粒细胞、血小板和网织红细胞）减少不那么剧烈和/或更快速恢复。这些结果支持 ADC 疏水性、非特异性摄取速率、释放有效负载的峰值组织浓度以及由此产生的毒理学参数之间的强相关性。如果这些相关性可以转化为临床，这将提供一种更通用、更容易处理的策略，通过药物接头设计调节非特异性生物分布来降低 ADC 的抗原非依赖性毒性。
Recently, we described a family of non-targeting monomethylauristatin E (MMAE) antibody-drug conjugates (ADCs) whose pharmacokinetics could be tuned through incorporation of a short polyethylene glycol (PEG) moiety of up to twelve units into a drug-linker to render the ADC surface more hydrophilic. That work demonstrated that more hydrophilic ADCs were simultaneously more effective and better tolerated in mouse models, suggesting an improvement in therapeutic index via this strategy. Here, we describe the biodistribution and toxicology assessments in Sprague-Dawley rats after intravenous dosing with the aim of elucidating the relationships between these biological outcomes and the underlying physicochemical properties of non-targeted ADCs. Dosing a non-PEGylated ADC exhibited rapid nonspecific cellular uptake, leading to ADC catabolism and rapid release of the cytotoxic payload which reached peak plasma and tissue concentrations within the first day. Introduction of a PEG chain of four, eight, or twelve units resulted in increasingly slower uptake and decreases in peak payload concentrations in all tissues. These ADCs with minimal non-specific uptake also exhibited substantially less hematologic toxicity, with reduced histologic depletion of bone marrow and less dramatic decreases and/or more rapid recovery in peripheral hematologic cell counts (neutrophils, platelets, and reticulocytes). These results support a strong correlation between ADC hydrophobicity, rate of non-specific uptake, peak tissue concentration of released payload, and resulting toxicology parameters. Should these correlations be translatable to the clinic, this would provide a more general and highly tractable strategy for reducing the antigen-independent toxicity of ADCs through drug-linker design to modulate non-specific biodistribution.