Abstract：
Antibody-enzyme conjugates have shown potential as tissue-specific prodrug activators by antibody-directed enzyme prodrug therapy (ADEPT), but the approach met challenges clinically due to systemic drug release. Here, we report a novel dual-targeting ADEPT system (DuADEPT) which is based on active cancer receptor targeting of both a trastuzumab-sialidase conjugate (Tz-Sia) and a highly potent sialidase-activated monomethyl auristatin E (MMAE) prodrug scaffold. The scaffold is based on a four-way junction of the artificial nucleic acid analog acyclic (L)-threoninol nucleic acid ((L)-aTNA) which at the ends of its four arms carries one nanobody targeting HER2 and three copies of the prodrug. Dual-targeting of the constructs to two proximal epitopes of HER2 was shown by flow cytometry, and a dual-targeted enzymatic drug release assay revealed cytotoxicity upon prodrug activation specifically for HER2-positive cancer cells. The specific delivery and activation of prodrugs in this way could potentially be used to decrease systemic side effects and increase drug efficacy, and utilization of Tz-Sia provides an opportunity to combine the local chemotherapeutic effect of the DuADEPT with an anticancer immune response.
摘要：
抗体-酶缀合物通过抗体定向酶前药疗法（ADEPT）显示出作为组织特异性前药激活剂的潜力，但由于全身性药物释放,该方法在临床上遇到了挑战.这里,我们报道了一种新型的双靶向ADEPT系统(DuADEPT),该系统基于曲妥珠单抗-唾液酸酶偶联物(Tz-Sia)和高效唾液酸酶激活的单甲基奥瑞他汀E(MMAE)前药支架的主动癌症受体靶向.支架基于人工核酸类似物无环(L)-苏氨酸醇核酸((L)-aTNA)的四向连接,其在其四个臂的末端携带靶向HER2的一个纳米抗体和三个拷贝的前药。通过流式细胞术显示构建体对HER2的两个近端表位的双重靶向,双靶向酶药物释放试验揭示了前药激活后对HER2阳性癌细胞特异性的细胞毒性。以这种方式的前药的特定递送和激活可能潜在地用于减少全身副作用并增加药物功效。Tz-Sia的利用提供了将DuADEPT的局部化疗效果与抗癌免疫应答相结合的机会。
