DARPin-targeting of Measles Virus: Unique Bispecificity, Effective Oncolysis, and Enhanced Safety
DARPin-targeting of Measles Virus: Unique Bispecificity, Effective Oncolysis, and Enhanced Safety
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DOI：
10.1038/mt.2013.16
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发表时间：
2013-04-01
影响因子：
12.4
通讯作者：
Muehlebach, Michael D.
中科院分区：
文献类型：
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作者：
Friedrich, Katrin;Hanauer, Jan R. H.;Muehlebach, Michael D.
溶瘤病毒疗法是一种新兴的治疗方式，它使用复制能力强的病毒来摧毁癌症。许多自然产生的病毒对肿瘤和肿瘤细胞有优先的、但非排他性的趋向性。此外，可以在病毒入门水平上实现对癌细胞的特定靶向。我们通过使用设计的锚蛋白重复蛋白(DARPins)延长麻疹病毒附着蛋白(DARPins)，同时通过自然受体去除细胞进入，从而优化了细胞进入的重定向。靶向Darpin的病毒在非靶向组织中被强烈减弱，从而提高了安全性，但完全消除了肿瘤移植。利用DARPins融合而不会产生折叠问题的独特特性，我们生成了一种同时针对两个不同肿瘤标记物的病毒。这种双特异性病毒保留了最初的溶瘤效果，同时为对抗耐药性发展问题的战略提供了概念证明。因此，DARPin靶向为个性化、靶向治疗的发展开辟了新的前景。2012年11月16日收到；2013年1月4日接受；2013年2月5日在线预发。DOI：10.1038/mt.2013.16
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Many naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. In addition, specific targeting of cancer cells can be achieved at the virus entry level. We optimized retargeting of cell entry by elongating the measles virus attachment protein with designed ankyrin repeat proteins (DARPins), while simultaneously ablating entry through the natural receptors. DARPin-targeted viruses were strongly attenuated in off-target tissue, thereby enhancing safety, but completely eliminated tumor xenografts. Taking advantage of the unique properties of DARPins of being fused without generating folding problems, we generated a virus simultaneous targeting two different tumor markers. The bispecific virus retained the original oncolytic efficacy, while providing proof of concept for a strategy to counteract issues of resistance development. Thus, DARPin-targeting opens new prospects for the development of personalized, targeted therapeutics. Received 16 November 2012; accepted 4 January 2013; advance online publication 5 February 2013. doi:10.1038/mt.2013.16