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.

中文翻译：

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通过最大程度地减少通过PEG化的非特异性清除，降低抗体-药物偶联物的抗原非依赖性毒性。

最近，我们描述了一个非靶向性单甲基auristatin E（MMAE）抗体-药物偶联物（ADCs）系列，其药代动力学可以通过将最多十二个单元的短聚乙二醇（PEG）部分掺入药物接头中进行调节ADC表面更亲水。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，这表明通过该策略可改善治疗指数。在这里，我们描述了静脉给药后Sprague-Dawley大鼠的生物分布和毒理学评估，目的是阐明这些生物学结果与非靶向ADC潜在的理化性质之间的关系。服用非PEG化的ADC表现出快速的非特异性细胞摄取，导致ADC分解代谢并迅速释放细胞毒性有效载荷，并在第一天内达到血浆和组织的峰值浓度。引入四个，八个或十二个单元的PEG链会导致吸收速度越来越慢，并且所有组织中的有效载荷峰值降低。这些具有最小非特异性摄取的ADC也表现出明显更少的血液学毒性，减少了骨髓的组织学耗竭，并且较少地降低了外周血液细胞计数（嗜中性粒细胞，血小板和网状细胞）和/或更快地恢复。这些结果支持ADC疏水性，非特异性摄取速率，释放的有效负载的组织峰值浓度和产生的毒理学参数之间的强相关性。这些相关性是否可以翻译到诊所，