title: Development of an oncolytic HSV vector fully retargeted specifically to cellular EpCAM for virus entry and cell-to-cell spread.
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.
authors.affiliation: Division of Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Division of Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Division of Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shiroyama
authors.affiliation: Division of Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okubo
authors.affiliation: Division of Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Hokkaido, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyagawa
authors.affiliation: Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fukuhara
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Cohen
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Glorioso
authors.affiliation: Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.|Section of Biochemistry, Department of Hard Tissue Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Watabe
authors.affiliation: Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.|Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Hokkaido, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hamada
authors.affiliation: Division of Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tahara
mesh_terms: D000818:Animals; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops / Q000276:immunology; D003412:Cricetulus; D000071858:Epithelial Cell Adhesion Molecule / Q000235:genetics* / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics* / Q000378:metabolism; D056945:Hep G2 Cells; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D000075983:Nectins; D009369:Neoplasms / Q000628:therapy* / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D011897:Random Allocation; D011991:Receptors, Virus / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D014162:Transfection / Q000379:methods; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization; D023041:Xenograft Model Antitumor Assays
chemical_list: D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D011991:Receptors, Virus; D057127:Single-Chain Antibodies; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1