title: Pseudotyped αvβ6 integrin-targeted adenovirus vectors for ovarian cancer therapies.
abstract: Encouraging results from recent clinical trials are revitalizing the field of oncolytic virotherapies. Human adenovirus type 5 (HAdV-C5/Ad5) is a common vector for its ease of manipulation, high production titers and capacity to transduce multiple cell types. However, effective clinical applications are hindered by poor tumor-selectivity and vector neutralization. We generated Ad5/kn48 by pseudotyping Ad5 with the fiber knob domain from the less seroprevalent HAdV-D48 (Ad48). The vector was shown to utilize coxsackie and adenovirus receptor (CAR) but not CD46 for cell entry. A 20-amino acid peptide NAVPNLRGDLQVLAQKVART (A20) was inserted into the Ad5. Luc HI loop (Ad5.HI.A20) and Ad5/kn48 DG loop (Ad5/kn48.DG.A20) to target a prognostic cancer cell marker, αvβ6 integrin. Relative to the Ad5.Luc parent vector, Ad5.HI.A20, Ad5.KO1.HI.A20 (KO1, ablated CAR-binding) and Ad5/kn48.DG.A20 showed ~ 160-, 270- and 180-fold increased transduction in BT-20 breast carcinoma cells (αvβ6high). Primary human epithelial ovarian cancer (EOC) cultures derived from clinical ascites provided a useful ex vivo model for intraperitoneal virotherapy. Ad5.HI.A20, Ad5.KO1.HI.A20 and Ad5/kn48.DG.A20 transduction was ~ 70-, 60- and 16-fold increased relative to Ad5.Luc in EOC cells (αvβ6high), respectively. A20 vectors transduced EOC cells at up to ~ 950-fold higher efficiency in the presence of neutralizing ovarian ascites, as compared to Ad5.Luc. Efficient transduction and enhanced cancer-selectivity via a non-native αvβ6-mediated route was demonstrated, even in the presence of pre-existing anti-Ad5 immunity. Consequently, αvβ6-targeted Ad vectors may represent a promising platform for local intraperitoneal treatment of ovarian cancer metastases.
authors.affiliation: Department of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Hanni
authors.initials: H
authors.lastname: Uusi-Kerttula
authors.affiliation: Department of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: James
authors.initials: J
authors.lastname: Davies
authors.affiliation: Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Lynda
authors.initials: L
authors.lastname: Coughlan
authors.affiliation: Department of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hulin-Curtis
authors.affiliation: Velindre Cancer Centre, Cardiff CF14 2TL, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Jones
authors.affiliation: Velindre Cancer Centre, Cardiff CF14 2TL, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Hanna
authors.affiliation: Department of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.|Velindre Cancer Centre, Cardiff CF14 2TL, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Chester
authors.affiliation: Department of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Parker
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics; D005818:Genetic Engineering / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007274:Injections, Intraperitoneal; D016023:Integrins / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000628:therapy*; D010455:Peptides / Q000235:genetics; D061251:Primary Cell Culture; D011379:Prognosis; D014161:Transduction, Genetic / Q000379:methods*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016023:Integrins; D010455:Peptides; C073878:integrin alphavbeta6
keywords: adenovirus; neutralizing antibody; ovarian cancer; re-targeting; αvβ6 integrin