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Development of an oncolytic HSV vector fully retargeted specifically to cellular EpCAM for virus entry and cell-to-cell spread

Gene Therapy volume 23, pages 479–488 (2016)Cite this article

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Abstract

Oncolytic herpes simplex virus (HSV) vectors have attracted increasing attention as novel anti-cancer agents. HSV entry is triggered by the binding of glycoprotein D (gD) to its receptors, such as herpesvirus entry mediator or nectin-1. We have recently reported the construction of a fully retargeted HSV platform that incorporates single-chain antibodies (scFv) into gD to mediate entry exclusively via tumor-associated antigens. In this study, we created an scFv directed against epithelial cell adhesion molecule (EpCAM), a recognized carcinoma-associated antigen, and inserted it into the retargeted HSV platform that is ablated for gD recognition of its canonical receptors and contains the entry-enhancing mutations in gB we previously identified. We observed that both initial entry and subsequent cell-to-cell spread of the retargeted virus were stringently dependent on cellular EpCAM expression. Interestingly, the retargeted virus developed larger plaques on some of the human tumor lines tested than the control virus bearing wild-type gD. Intratumoral injection of the retargeted virus revealed antitumor activity in a mouse xenograft model. These observations illustrate the versatility of our retargeted HSV platform as it allows expansion of the oncolytic virus toolbox for the treatment of diverse cancers.

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Acknowledgements

We thank Drs David Leib, Nikolaus Osterrieder, Patricia Spear, Gary Cohen, Roselyn Eisenberg, Stephen Russell, Izumi Kumagai and Toshio Kitamura for reagents. We also thank Drs Kiyoko Fukami, Masato Tanaka, Katsuko Tani, Nobuko Matsushita and Yasuhiro Yoshimatsu (Tokyo University of Pharmacy and Life Sciences) for helpful discussions. This work was supported in part by JSPS KAKENHI grant numbers 23800058, 25290059 and 15K15144, the Suzuken Memorial Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, The Research Foundation for Pharmaceutical Sciences, Takeda Science Foundation, The Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, The Sumitomo Foundation and the Pancreas Research Foundation of Japan. YM, JBC and JCG were supported by NIH grant CA163205.

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Authors and Affiliations

  1. Division of Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    T Shibata, H Uchida, T Shiroyama, Y Okubo, T Suzuki, H Ikeda & H Tahara

  2. Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

    T Shibata, H Uchida, T Shiroyama, Y Okubo, T Suzuki, H Ikeda, T Fukuhara, T Watabe & H Hamada

  3. Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Hokkaido, Japan

    M Yamaguchi & H Hamada

  4. Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Y Miyagawa, J B Cohen & J C Glorioso

  5. Department of Hard Tissue Engineering, Section of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    T Watabe

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  1. T Shibata
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Correspondence to H Uchida.

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Shibata, T., Uchida, H., Shiroyama, T. et al. Development of an oncolytic HSV vector fully retargeted specifically to cellular EpCAM for virus entry and cell-to-cell spread. Gene Ther 23, 479–488 (2016). https://doi.org/10.1038/gt.2016.17

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