Mersana Therapeutics, Inc., Cambridge, Massachusetts.
Formerly Mersana Therapeutics, Inc., Cambridge, Massachusetts.
Mol Cancer Ther. 2024 Apr 2;23(4):541-551. doi: 10.1158/1535-7163.MCT-23-0622.
Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), 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 cross-linking. 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 multidrug resistant (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.
尽管微管抑制剂 (MTI) 仍然是抗体药物偶联物 (ADC) 的一种有治疗价值的有效载荷选择，但有些癌症对基于 MTI 的 ADC 没有反应。为了填补这一治疗空白，最近 ADC 有效载荷“工具箱”得到了扩展，其中包括具有拓扑异构酶抑制和 DNA 交联等新型作用机制的有效载荷。我们在这里介绍了一种新型 DNA 单烷化剂 ADC 平台的开发，该平台在 MTI 耐药肿瘤中单次给药即可持续抑制肿瘤生长，并且在大鼠中重复给药时具有良好的耐受性。有效载荷的磷酰胺前药使 ADC 即使在 5:1 的药物抗体比下也能保持低聚集，同时仍能提供旁观者有效载荷，在多药耐药 (MDR) 过表达细胞系中有效。该平台在异种移植研究中与临床基准 DNA 单烷化剂 ADC 平台 DGN459 相当，但在大鼠中的耐受性明显更好。因此，该新平台的活性和耐受性使其成为开发 ADC 的可行选择。
