Pseudotyped αvβ6 integrin-targeted adenovirus vectors for ovarian cancer therapies

Uusi-Kerttula, Hanni, Davies, James, Coughlan, Lynda, Hulin-Curtis, Sarah L ORCID: 0000-0003-0889-964X, Jones, Rachel, Hanna, Louise, Chester, John D and Parker, Alan L (2016) Pseudotyped αvβ6 integrin-targeted adenovirus vectors for ovarian cancer therapies. Oncotarget, 7 (19). pp. 27926-27937. doi:10.18632/oncotarget.8545

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Text 14147 Uusi-Kerttula, Davies, Coughlan, Hulin-Curtis, Jones, Hanna, Chester, Parker (2016) Pseudotyped avB6 integrin-targeted adenovirus vectors for ovarian cancer therapies.pdf - Published Version Available under License Creative Commons Attribution 4.0. Download (4MB) | Preview

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, avβ6 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 (avβ6high). 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 (avβ6high), 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 avβ6-mediated route was demonstrated, even in the presence of pre-existing anti-Ad5 immunity. Consequently, avβ6-targeted Ad vectors may represent a promising platform for local intraperitoneal treatment of ovarian cancer metastases.

Item Type:	Article
Article Type:	Article
Uncontrolled Keywords:	Adenovirus; Re-targeting; Neutralizing antibody; Ovarian cancer; αvβ6 integrin
Subjects:	R Medicine > R Medicine (General)
Divisions:	Schools and Research Institutes > School of Education and Science
Research Priority Areas:	Health, Life Sciences, Sport and Wellbeing
Depositing User:	Sarah Curtis
Date Deposited:	17 Jun 2024 09:31
Last Modified:	17 Jun 2024 09:45
URI:	https://eprints.glos.ac.uk/id/eprint/14147

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