title: A vesicular stomatitis virus glycoprotein epitope-incorporated oncolytic adenovirus overcomes CAR-dependency and shows markedly enhanced cancer cell killing and suppression of tumor growth.
abstract: Utility of traditional oncolytic adenovirus (Ad) has been limited due to low expression of coxsackie and adenovirus receptor (CAR) in cancer cells which results in poor infectivity of Ads. Here with an aim of improving the efficiency of Ad's entry to the cell, we generated a novel tropism-expanded oncolytic Ad which contains the epitope of vesicular stomatitis virus glycoprotein (VSVG) at the HI-loop of Ad fiber. We generated 9 variants of oncolytic Ads with varying linkers and partial deletion to the fiber. Only one VSVG epitope-incorporated variant, RdB-1L-VSVG, which contains 1 linker and no deletion to fiber, was produced efficiently. Production of 3-dimensionaly stable fiber in RdB-1L-VSVG was confirmed by immunoblot analysis. RdB-1L-VSVG shows a remarkable improvement in cytotoxicity and total viral yield in cancer cells. RdB-1L-VSVG demonstrates enhanced cytotoxicity in cancer cells with subdued CAR-expression as it can be internalized by an alternate pathway. Competition assays with a CAR-specific antibody (Ab) or VSVG receptor, phosphatidyl serine (PS), reveals that cell internalization of RdB-1L-VSVG is mediated by both CAR and PS. Furthermore, treatment with RdB-1L-VSVG significantly enhanced anti-tumor effect in vivo. These studies demonstrate that the strategy to expand oncolytic Ad tropism may significantly improve therapeutic profile for cancer treatment.
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seongdong-gu, Seoul 133-791, Korea.
authors.forename: A-Rum
authors.initials: AR
authors.lastname: Yoon
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seongdong-gu, Seoul 133-791, Korea.
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seongdong-gu, Seoul 133-791, Korea.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D000939:Epitopes / Q000235:genetics; D005822:Genetic Vectors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D014161:Transduction, Genetic; D014759:Viral Envelope Proteins / Q000235:genetics*; D053586:Virus Internalization; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D000939:Epitopes; C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins
keywords: CAR dependency; VSVG; fiber; oncolytic adenovirus; therapeutic efficacy