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

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 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.

SUBMITTER: Bates EA

PROVIDER: S-EPMC8971729 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Bates Emily A EA Davies James A JA Váňová Jana J Nestić Davor D Meniel Valerie S VS Koushyar Sarah S Cunliffe Tabitha G TG Mundy Rosie M RM Moses Elise E Uusi-Kerttula Hanni K HK Baker Alexander T AT Cole David K DK Majhen Dragomira D Rizkallah Pierre J PJ Phesse Toby T Chester John D JD Parker Alan L AL

Molecular therapy oncolytics 20220316

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 en ...[more]

PMID: 35399606

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Dataset Information

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

Publications

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

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