Antibody-drug conjugates (ADCs) are a well-established class of therapeutics primarily used in oncology to selectively deliver highly cytotoxic agents into cancer cells. While ADCs should theoretically spare healthy tissues and diminish side effects in patients, off-target toxicity is still observed, all the more serious, as the drugs are extremely potent. In the quest toward safer payloads, we used the conventional chemotherapeutic drug vincristine to develop antibody-vincristine conjugates. Vincristine was N-alkylated with a cleavable linker and the resulting linker-payload conjugated to free cysteines of antibodies. We show that trastuzumab-vincristine conjugates display subnanomolar potency in vitro on HER2-positive cells, 2 orders of magnitude lower than free vincristine and comparable with marketed ADC. In vivo, trastuzumab-vincristine conjugates led to remarkable efficacy when compared to two standards of care, with complete tumor regression just 9 days after single administration. This highlights the untapped potential of the chemotherapeutic arsenal toward the development of novel ADC.

中文翻译：

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抗体-长春新碱偶联物作为有效的抗癌治疗剂


抗体-药物偶联物 （ADC） 是一类成熟的治疗方法，主要用于肿瘤学，选择性地将高细胞毒性药物输送到癌细胞中。虽然 ADC 理论上应该保留健康组织并减少患者的副作用，但仍然观察到脱靶毒性，而且由于药物非常有效，因此更加严重。为了寻求更安全的有效载荷，我们使用传统的化疗药物长春新碱来开发抗体-长春新碱偶联物。长春新碱用可切割的连接子进行 N-烷基化，所得的连接子有效载荷与抗体的游离半胱氨酸偶联。我们表明，曲妥珠单抗-长春新碱偶联物在体外对 HER2 阳性细胞表现出亚纳摩尔效力，比游离长春新碱低 2 个数量级，与市售的 ADC 相当。在体内，与两种标准治疗相比，曲妥珠单抗-长春新碱偶联物具有显着的疗效，单次给药后仅 9 天肿瘤完全消退。这凸显了化疗药物库在开发新型 ADC 方面尚未开发的潜力。