Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody drug conjugates (ADCs), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA crosslinking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well-tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug to antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in MDR-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.

中文翻译：

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用于抗体药物偶联物的新型 DNA 单烷基化平台的开发

尽管微管抑制剂 (MTI) 仍然是抗体药物偶联物 (ADC) 具有治疗价值的有效负载选择，但某些癌症对基于 MTI 的 ADC 没有反应。为了填补这一治疗空白，最近 ADC 有效负载“工具箱”得到了扩展，其中包括具有拓扑异构酶抑制和 DNA 交联等新颖作用机制的有效负载。我们在这里展示了一种新型 DNA 单烷基化剂 ADC 平台的开发，该平台在单剂量下对 MTI 耐药肿瘤表现出持续的肿瘤生长抑制作用，并且在重复给药后在大鼠中具有良好的耐受性。有效负载的氨基磷酸酯前药即使在药物与抗体比例为 5:1 的情况下也能实现低 ADC 聚集，同时仍然提供对 MDR 过表达细胞系有效的旁观者可用的有效负载。该平台在异种移植研究中与临床基准 DNA 单烷基化器 ADC 平台 DGN459 相当，但在大鼠中具有明显更好的耐受性。因此，这个新平台的活性和耐受性使其成为 ADC 开发的可行选择。