| Structural highlights
Publication Abstract from PubMed
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 alphavbeta6 integrin-selective peptide, A20, to target alphavbeta6-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 alphavbeta6 integrin into the DG loop of HAdV-D10 fiber knob. Assays in alphavbeta6+ cancer cell lines demonstrated significantly increased transduction mediated by alphavbeta6-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 alphavbeta6 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 alphavbeta6 integrin-selective peptide resulted in HAdV-D10.A20, with significant potential for clinical translation.
Development of a low-seroprevalence, alphavbeta6 integrin-selective virotherapy based on human adenovirus type 10.,Bates EA, Davies JA, Vanova J, Nestic D, Meniel VS, Koushyar S, Cunliffe TG, Mundy RM, Moses E, Uusi-Kerttula HK, Baker AT, Cole DK, Majhen D, Rizkallah PJ, Phesse T, Chester JD, Parker AL Mol Ther Oncolytics. 2022 Mar 16;25:43-56. doi: 10.1016/j.omto.2022.03.007., eCollection 2022 Jun 16. PMID:35399606[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bates EA, Davies JA, Vanova J, Nestic D, Meniel VS, Koushyar S, Cunliffe TG, Mundy RM, Moses E, Uusi-Kerttula HK, Baker AT, Cole DK, Majhen D, Rizkallah PJ, Phesse T, Chester JD, Parker AL. Development of a low-seroprevalence, alphavbeta6 integrin-selective virotherapy based on human adenovirus type 10. Mol Ther Oncolytics. 2022 Mar 16;25:43-56. doi: 10.1016/j.omto.2022.03.007., eCollection 2022 Jun 16. PMID:35399606 doi:http://dx.doi.org/10.1016/j.omto.2022.03.007
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