Bispecific Adapter-Mediated Retargeting of a Receptor-Restricted HSV-1 Vector to CEA-Bearing Tumor Cells
Bispecific Adapter-Mediated Retargeting of a Receptor-Restricted HSV-1 Vector to CEA-Bearing Tumor Cells
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DOI：
10.1038/mt.2010.207
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发表时间：
2011-03-01
影响因子：
12.4
通讯作者：
Kwon, Heechung
中科院分区：
文献类型：
--
作者：
Baek, Hyunjung;Uchida, Hiroaki;Kwon, Heechung
通过将病毒感染重定向至肿瘤特异性细胞表面标志物，可以增强病毒治疗实体瘤的安全性和有效性。单纯疱疹病毒1型（HSV-1）的成功重靶向已实现使用载体，携带修饰的包膜糖蛋白D（gD）工程直接与新的受体相互作用。此外，可溶性桥接分子（衔接子）已被用于间接连接gD细胞特异性受体。在这里，我们描述了一个适配器连接gD的共同肿瘤抗原癌胚抗原（CEA）的发展。衔接子由CEA特异性单链抗体与gD受体的gD结合区（疱疹病毒进入介体（HVEM））融合组成。我们将该衔接子与载体组合使用，所述载体是去靶向的，用于识别广泛表达的gD受体nectin-1，但保留不太常见的HVEM的完整结合区。我们表明，适配器能够感染HSV-抗性中国仓鼠卵巢（CHO）细胞表达异位CEA和nectin-1/CEA-轴承人胃癌细胞是耐单独的载体。我们观察到衔接子介导的体外感染后细胞间的扩散，并减少了体内肿瘤的生长，表明这种载体重靶向的方法可能为肿瘤特异性递送杀肿瘤HSV提供了一种新的策略。
The safety and efficacy of viral therapies for solid tumors can be enhanced by redirecting the virus infection to tumor-specific cell-surface markers. Successful retargeting of herpes simplex virus type 1 (HSV-1) has been achieved using vectors that carry a modified envelope glycoprotein D (gD) engineered to interact directly with novel receptors. In addition, soluble bridging molecules (adapters) have been used to link gD indirectly to cellspecific receptors. Here, we describe the development of an adapter connecting gD to the common tumor antigen carcinoembryonic antigen (CEA). The adapter consisted of a CEA-specific single-chain antibody fused to the gD-binding region of the gD receptor, herpes virus entry mediator (HVEM). We used this adapter in combination with a vector that is detargeted for recognition of the widely expressed gD receptor nectin-1, but retains an intact binding region for the less common HVEM. We show that the adapter enabled infection of HSV-resistant Chinese hamster ovary (CHO) cells expressing ectopic CEA and nectin-1/CEA-bearing human gastric carcinoma cells that are resistant to the vector alone. We observed cell-to-cell spread following adapter-mediated infection in vitro and reduced tumor growth in vivo, indicating that this method of vector retargeting may provide a novel strategy for tumor-specific delivery of tumoricidal HSV.