title: Infectivity-selective oncolytic adenovirus developed by high-throughput screening of adenovirus-formatted library.
abstract: Adenovirus (Ad) is a potent gene-delivery vehicle and has frequently been used for designing oncolytic viruses. However, lack of selectivity on infection has hampered the achievement of sufficient in vivo efficiency. Here, we developed a novel oncolytic virus system, infectivity-selective oncolytic adenovirus (ISOAd), via direct high-throughput screening of a high-diversity targeting-ligand library in adenoviral format. Through our newly designed rescue virus system, the high-diversity Ad library carrying the random seven amino acid sequences ligand-library in the AB-loop of its fiber-knob region (5 × 10(9) diversity) was successfully generated. During the screening of this library with the cells expressing the target molecule (mesothelin, MSLN), the AB-loop sequence of the virus clones converged to one dominant sequence and a novel MSLN-targeting sequence was isolated. The virus with the isolated motif showed selective infectivity to MSLN-positive cells in vitro. In vivo, it exhibited a selective and potent antitumor effect resulted from the viral replication in MSLN-positive xenografts. The ISOAd is a novel class of oncolytic Ad, which has selectivity at the step of transduction. The selectivity at the stage of infection can open new perspectives in oncolytic Ad therapy for various diseases.
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Julia
authors.initials: J
authors.lastname: Davydova
authors.forename: Eric
authors.initials: E
authors.lastname: Brown
authors.forename: Kazunori
authors.initials: K
authors.lastname: Aoki
authors.forename: Selwyn
authors.initials: S
authors.lastname: Vickers
authors.forename: Masato
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000256:Adenoviridae / Q000472:pathogenicity*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000090204:Mesothelin; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D050130:Oncolytic Virotherapy; D016133:Polymerase Chain Reaction; D014774:Virulence
chemical_list: D017931:DNA Primers; C000715527:MSLN protein, human; C000715528:Msln protein, mouse; D000090204:Mesothelin