National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Drug Deliv. 2022 Dec;29(1):754-766. doi: 10.1080/10717544.2022.2039807.
Maleimides are typically applicable for coupling with reactive thiol moieties of antibodies in antibody-drug conjugates (ADCs) via the thiol-Michael click chemistry. Even so, the thiosuccinimide group produced in ADCs is unstable under physiological conditions, which is a unresolved issue in the ADC industry that can cause serious off-target toxicity. Committed to solving the stability defects of traditional thiosuccinimide-containing ADCs, we explored a series of linkers based on the ring-opening hydrolysates of thiosuccinimide. Meanwhile, a type of linkers based on maleamic methyl ester were used to conjugate the popular monomethyl auristatin E to an anti-HER2 antibody to generate the target ADCs, which enhances the stability and do not need to change the structure of the ideal stable metabolite of traditional ADCs. studies demonstrate that our preferred ADC mil40- not only has better efficacy than traditional ADCs but also exhibits better safety parameters in mice. For example, complete tumor regression can still be achieved even when the dose is halved (2.5 mg/kg), and the maximum tolerable dose is increased by 40 mg/kg. This strategy is expected to provide an applicable tool for the construction of thiol-linked ADCs with improved therapeutic index.
马来酰亚胺通常适用于通过硫醇-Michael 点击化学将抗体药物偶联物 (ADC) 中的反应性巯基部分与抗体偶联。即便如此，ADC 中产生的硫代琥珀酰亚胺基团在生理条件下不稳定，这是 ADC 行业中尚未解决的问题，可能导致严重的脱靶毒性。为了解决传统含硫代琥珀酰亚胺 ADC 的稳定性缺陷，我们探索了一系列基于硫代琥珀酰亚胺开环水解产物的连接子。同时，我们使用基于马来酰亚胺甲酯的一类连接子将流行的单甲基奥瑞他汀 E 与抗 HER2 抗体偶联，生成目标 ADC，从而提高了稳定性，且无需改变传统 ADC 理想稳定代谢物的结构。研究表明，我们首选的 ADC mil40-不仅比传统 ADC 具有更好的疗效，而且在小鼠中还表现出更好的安全参数。例如，即使剂量减半（2.5mg/kg），也能完全实现肿瘤消退，并且最大耐受剂量增加了 40mg/kg。该策略有望为构建具有改善治疗指数的硫醇连接 ADC 提供一种实用工具。
