Cutaneous melanoma is one of the cancers with the fastest rising incidence and in its advanced metastatic form is a highly lethal disease. Despite the recent approval of several new drugs, the 5-year overall survival rate for advanced cutaneous melanoma is still below 20% and therefore, the development of novel treatments remains a primary need. Antibody-Drug Conjugates are an emerging novel class of anticancer agents, whose preclinical and clinical development has recently seen a remarkable increase in different tumors, including melanoma. Here, we have coupled the anti-HER-3 internalizing antibody EV20 to the cytotoxic drug monomethyl auristatin F (MMAF) to form a novel antibody-drug conjugate (EV20/MMAF). In a panel of human melanoma cell lines, this novel ADC shows a powerful, specific and target-dependent cell killing activity, independently of BRAF status. Efficacy studies demonstrated that a single administration of EV20/MMAF leads to a long-lasting tumor growth inhibition. Remarkably, the effect of this novel ADC was superior to the BRAF inhibitor vemurafenib in preventing kidney, liver and lung melanoma metastases. Overall, these results highlight EV20/MMAF as a novel ADC with promising therapeutic efficacy, warranting extensive pre-clinical evaluation in melanoma with high levels of HER-3 expression.

皮肤黑色素瘤是发病率上升最快的癌症之一，其晚期转移形式是一种高度致命的疾病。尽管最近批准了多种新药，但晚期皮肤黑色素瘤的 5 年总体生存率仍低于 20%，因此，开发新的治疗方法仍然是首要需求。抗体药物偶联物是一类新兴的新型抗癌药物，其临床前和临床开发最近在包括黑色素瘤在内的不同肿瘤中显着增加。在这里，我们将抗 HER-3 内化抗体 EV20 与细胞毒性药物单甲基 auristatin F (MMAF) 偶联，形成新型抗体-药物缀合物 (EV20/MMAF)。在一组人类黑色素瘤细胞系中，这种新型 ADC 显示出强大的、特异性的、靶点依赖性的细胞杀伤活性，与 BRAF 状态无关。功效研究表明，单次施用 EV20/MMAF 即可实现持久的肿瘤生长抑制。值得注意的是，这种新型 ADC 在预防肾、肝和肺黑色素瘤转移方面的效果优于 BRAF 抑制剂维莫非尼 (vemurafenib)。总体而言，这些结果凸显了 EV20/MMAF 作为一种新型 ADC，具有良好的治疗效果，值得对具有高水平 HER-3 表达的黑色素瘤进行广泛的临床前评估。