title: Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors.
abstract: Conditionally replicative adenoviruses (CRAds) are potentially useful agents for anticancer virotherapy approaches. However, lack of coxsackievirus and adenovirus receptor (CAR) expression on many primary tumor cells limits the oncolytic potency of CRAds. This makes the concept of targeting, that is, redirecting infection via CAR-independent entry pathways, relevant for CRAd development. Bispecific adapter molecules constitute highly versatile means for adenovirus targeting. Here, we constructed a CRAd with the Delta24 E1A mutation that produces a bispecific single-chain antibody directed towards the adenovirus fiber knob and the epidermal growth factor receptor (EGFR). This EGFR-targeted CRAd exhibited increased infection efficiency and oncolytic replication on CAR-deficient cancer cells and augmented lateral spread in CAR-deficient 3-D tumor spheroids in vitro. When compared to its parent control with native tropism, the new CRAd exhibited similar cytotoxicity on CAR-positive cancer cells, but up to 1000-fold enhanced oncolytic potency on CAR-deficient, EGFR-positive cancer cells. In addition, EGFR-targeted CRAd killed primary human CAR-deficient brain tumor specimens that were refractory to the parent control virus. We conclude, therefore, that CRAds expressing bispecific targeting adapter molecules are promising agents for cancer treatment. Their use is likely to result in enhanced oncolytic replication in cancerous tissues and thus in more effective tumor regression.
authors.affiliation: Division of Gene Therapy, Department of Medical Oncology, The Netherlands.
authors.forename: V W
authors.initials: VW
authors.lastname: van Beusechem
authors.forename: D C J
authors.initials: DC
authors.lastname: Mastenbroek
authors.forename: P B
authors.initials: PB
authors.lastname: van den Doel
authors.forename: M L M
authors.initials: ML
authors.lastname: Lamfers
authors.forename: J
authors.initials: J
authors.lastname: Grill
authors.forename: T
authors.initials: T
authors.lastname: Würdinger
authors.forename: H J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: W R
authors.initials: WR
authors.lastname: Gerritsen
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011991:Receptors, Virus / Q000172:deficiency / Q000235:genetics*; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007141:Immunoglobulin Fc Fragments; D011991:Receptors, Virus; D066246:ErbB Receptors