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Development of a low seroprevalence, αvβ6 integrin selective virotherapy based on human adenovirus type 10

Bates, Emily A., Davies, James A., Vánová, Jana, Nestic, Davor, Meniel, Valerie S., Koushyar, Sarah, Cunliffe, Tabitha G., Mundy, Rosie M., Moses, Elise, Uusi-Kerttula, Hanni K., Baker, Alexander T., Cole, David K., Majhen, Dragomira, Rizkallah, Pierre J., Phesse, Toby, Chester, John D. and Parker, Alan L. 2022. Development of a low seroprevalence, αvβ6 integrin selective virotherapy based on human adenovirus type 10. Molecular Therapy - Oncolytics 25 , pp. 43-56. 10.1016/j.omto.2022.03.007

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Abstract

Oncolytic virotherapies (OV) hold immense clinical potential. OV based on human adenoviruses (HAdV) derived from HAdV with naturally low rates of pre-existing immunity will be beneficial for future clinical translation. We generated a low seroprevalence HAdV-D10 serotype vector incorporating an αvβ6 integrin selective peptide, A20, to target αvβ6 positive tumour cell types. HAdV-D10 has limited natural tropism. Structural and biological studies of HAdV-D10 knob protein highlighted low affinity engagement with native adenoviral receptors CAR and sialic acid. HAdV-D10 fails to engage blood coagulation Factor X, potentially eliminating “off-target” hepatic sequestration in vivo. We engineered A20 peptide that selectively binds αvβ6 integrin into the DG loop of HAdV-D10 fiber knob. Assays in αvβ6+ cancer cell lines, demonstrated significantly increased transduction mediated by αvβ6 targeted variants compared to controls, confirmed microscopically. HAdV-D10.A20 resisted neutralization by neutralizing HAdV-C5 sera. Systemic delivery of HAdV-D10.A20 resulted in significantly increased GFP expression in BT20 tumours. Replication competent HAdV-D10.A20 demonstrated αvβ6 integrin selective cell killing in vitro and in vivo. HAdV-D10 possesses characteristics of a promising virotherapy, combining low seroprevalence, weak receptor interactions and reduced off-target uptake. Incorporation of an αvβ6 integrin selective peptide resulted in HAdV-D10.A20, with significant potential for clinical translation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Publisher: Cell Press
ISSN: 2372-7705
Funders: Cancer Research UK
Date of First Compliant Deposit: 17 March 2022
Date of Acceptance: 13 March 2022
Last Modified: 30 Apr 2022 16:10
URI: https://orca.cardiff.ac.uk/id/eprint/148429

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