Measles viruses (MV) are rapidly inactivated by anti-measles neutralizing antibodies, which has limited their clinical performance as oncolytic agents. Here, by substituting the H and F surface glycoproteins of MV with those from the homologous canine distemper virus (CDV) and engineering the CDV H attachment protein to target EGFR or CD38, we generated a fully retargeted MV capable of resisting neutralization by measles-immune human serum. The resultant recombinant MVs encoding retargeted CDV envelope glycoproteins had similar growth kinetics as the control MV, showed the expected engineered receptor specificities for cell entry, intercellular fusion, and target cell killing, and were blind to native CDV receptors. In contrast to the control MV, recombinant MVs incorporating CDV F and H glycoproteins retained full infectivity when exposed to high concentrations of pooled measles-immune human serum. Comparing viruses bearing MV or CDV glycoproteins in the SKOV3ip.1 model, only the virus bearing an EGFR-retargeted CDV envelope glycoprotein complex was capable of limiting tumor growth and extending the survival in measles immune mice. MV, “stealthed” and retargeted using engineered CDV surface glycoproteins, may be a promising platform to advance for systemic cancer therapy in measles immune patients.

中文翻译：

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用于麻疹免疫患者全身癌症治疗的重新靶向和隐形修饰的溶瘤麻疹病毒

麻疹病毒 (MV) 被抗麻疹中和抗体迅速灭活，这限制了它们作为溶瘤剂的临床性能。在这里，通过用同源犬瘟热病毒 (CDV) 的 H 和 F 表面糖蛋白替换 MV 的 H 和 F 表面糖蛋白，并改造 CDV H 附着蛋白以靶向 EGFR 或 CD38，我们生成了能够抵抗麻疹免疫中和的完全重新靶向的 MV。人血清。所得的编码重新靶向 CDV 包膜糖蛋白的重组 MV 与对照 MV 具有相似的生长动力学，显示出预期的工程化受体特异性，用于细胞进入、细胞间融合和靶细胞杀伤，并且对天然 CDV 受体不敏感。对比对照MV，当暴露于高浓度混合麻疹免疫人血清时，包含 CDV F 和 H 糖蛋白的重组 MV 保持完全感染性。比较 SKOV3ip.1 模型中携带 MV 或 CDV 糖蛋白的病毒，只有携带 EGFR 重定向的 CDV 包膜糖蛋白复合物的病毒能够限制肿瘤生长并延长麻疹免疫小鼠的存活率。MV，使用工程化的 CDV 表面糖蛋白“隐藏”和重新定位，可能是推进麻疹免疫患者全身癌症治疗的有前途的平台。