Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zurich, Switzerland.
Philochem AG, Otelfingen, Switzerland.
Mol Cancer Ther. 2014 Nov;13(11):2641-52. doi: 10.1158/1535-7163.MCT-14-0599. Epub 2014 Sep 9.
The combination of immunostimulatory agents with cytotoxic drugs is emerging as a promising approach for potentially curative tumor therapy, but advances in this field are hindered by the requirement of testing individual combination partners as single agents in dedicated clinical studies, often with suboptimal efficacy. Here, we describe for the first time a novel multipayload class of targeted drugs, the immunocytokine-drug conjugates (IDC), which combine a tumor-homing antibody, a cytotoxic drug, and a proinflammatory cytokine in the same molecular entity. In particular, the IL2 cytokine and the disulfide-linked maytansinoid DM1 microtubular inhibitor could be coupled to the F8 antibody, directed against the alternatively spliced EDA domain of fibronectin, in a site-specific manner, yielding a chemically defined product with selective tumor-homing performance and potent anticancer activity in vivo, as tested in two different immunocompetent mouse models.
免疫刺激剂与细胞毒性药物的联合应用正成为一种有前途的潜在治愈性肿瘤治疗方法，但该领域的进展受到需要将各个联合药物作为单一药物在专门的临床研究中进行测试的限制，其疗效往往并不理想。在这里，我们首次描述了一类新型的多载药靶向药物，即免疫细胞因子-药物偶联物（IDC），它将肿瘤归巢抗体、细胞毒性药物和促炎细胞因子结合在同一分子实体中。具体来说，白细胞介素 2（IL2）细胞因子和二硫键连接的美登素 DM1 微管抑制剂可以以特定的方式与针对纤维连接蛋白的交替拼接 EDA 结构域的 F8 抗体偶联，得到一种具有选择性肿瘤归巢性能和体内强大抗癌活性的化学定义产物，在两种不同的免疫功能正常的小鼠模型中进行了测试。
