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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.; Vanova, Jana; Nestić, 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; 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. ISSN 2372-7705

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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 tumor 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 an 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 with 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 tumors. 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
Uncontrolled Keywords: oncolytic ; virotherapy ; adenovirus targeting ; αvβ6 integrin ; low seroprevalence ; structure
Subjects: NATURAL SCIENCES > Biology
Divisions: Division of Molecular Biology
Project titleProject leaderProject codeProject type
Endocitoza adenovirusa i urođeni imunosni odgovorMajhen, DragomiraIP-2019-04-6048HRZZ
Depositing User: Davor Nestić
Date Deposited: 26 Apr 2022 12:32
DOI: 10.1016/j.omto.2022.03.007

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