title: A strategy for systemic delivery of the oncolytic herpes virus HSV1716: redirected tropism by antibody-binding sites incorporated on the virion surface as a glycoprotein D fusion protein.
abstract: We report on the ability of single-chain variable fragment (scFv) incorporated into the viral envelope to alter the tropism of herpes simplex virus (HSV) 1716. Using recombinant viruses expressing fusion proteins comprising cell-surface antigen-specific scFvs N terminus linked to amino acids 274-393 of gD, we demonstrated that the tropism of these HSV1716 variants was modified such that infection was mediated by the cognate antigen. Thus, an HSV1716 variant that expressed an anti-CD55 scFv targeting moiety linked to these gD residues was able to infect non-permissive Chinese hamster ovary cells expressing CD55 and this infection was specifically blocked by an anti-CD55 monoclonal antibody. Similarly, the infection efficiency of an HSV1716 variant for semi-permissive human leukaemic, CD38-positive cell lines was greatly improved by an anti-CD38 scFv targeting moiety linked to gD residues 274-393, and this enhanced infectivity was abrogated specifically by an anti-CD38 monoclonal antibody. Finally, intravenous/intraperitoneal injection of an HSV1716 variant displaying an anti-epidermal growth factor receptor (EGFR) scFv linked to residues 274-393 of gD enhanced destruction of subcutaneous EGFR-positive tumours in nude mice compared to unmodified HSV1716. Therefore, targeting of HSV1716 oncolysis to specific cell types through the display of entry mediating scFv/gD fusion proteins represents an efficient route for systemic delivery.
authors.affiliation: Crusade Laboratories Ltd, Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland, UK. jconner@crusadelabs.co.uk
authors.forename: J
authors.initials: J
authors.lastname: Conner
authors.forename: L
authors.initials: L
authors.lastname: Braidwood
authors.forename: S M
authors.initials: SM
authors.lastname: Brown
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology; D000818:Animals; D001666:Binding Sites, Antibody / Q000235:genetics*; D018958:CD55 Antigens / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000276:immunology; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy / Q000379:methods*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D018139:Simplexvirus / Q000235:genetics*
chemical_list: D018958:CD55 Antigens; D006023:Glycoproteins; D007135:Immunoglobulin Variable Region; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors; D051997:ADP-ribosyl Cyclase 1