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

Bates, Emily A., Davies, James A. ORCID: https://orcid.org/0000-0003-3569-4500, Vánová, Jana, Nestic, Davor, Meniel, Valerie S., Koushyar, Sarah, Cunliffe, Tabitha G., Mundy, Rosie M., Moses, Elise, Uusi-Kerttula, Hanni K., Baker, Alexander T. ORCID: https://orcid.org/0000-0001-8232-0531, Cole, David K. ORCID: https://orcid.org/0000-0003-0028-9396, Majhen, Dragomira, Rizkallah, Pierre J. ORCID: https://orcid.org/0000-0002-9290-0369, Phesse, Toby ORCID: https://orcid.org/0000-0001-9568-4916, Chester, John D. ORCID: https://orcid.org/0000-0002-7830-3840 and Parker, Alan L. ORCID: https://orcid.org/0000-0002-9302-1761 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 European Cancer Stem Cell Research Institute (ECSCRI)
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:	11 Oct 2023 21:20
URI:	https://orca.cardiff.ac.uk/id/eprint/148429

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