Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors

V. W. van Beusechem, D. C J Mastenbroek, P. B. van den Doel, M. L M Lamfers, J. Grill, T. Würdinger, H. J. Haisma, H. M. Pinedo, W. R. Gerritsen

Research output: Contribution to journalArticle

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 Δ24 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.

Original languageEnglish (US)
Pages (from-to)1982-1991
Number of pages10
JournalGene Therapy
Volume10
Issue number23
DOIs
StatePublished - Nov 2003
Externally publishedYes

Fingerprint

Enterovirus
Adenoviridae
Neoplasms
Epidermal Growth Factor Receptor
Coxsackievirus Infections
adenovirus receptor
Bispecific Antibodies
Human Adenoviruses
Single-Chain Antibodies
Tropism
Brain Neoplasms
Antineoplastic Agents
Viruses
Mutation

Keywords

  • Adenovirus
  • Cancer
  • CAR
  • EGFR
  • Targeting
  • Virotherapy

ASJC Scopus subject areas

  • Genetics

Cite this

van Beusechem, V. W., Mastenbroek, D. C. J., van den Doel, P. B., Lamfers, M. L. M., Grill, J., Würdinger, T., ... Gerritsen, W. R. (2003). Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. Gene Therapy, 10(23), 1982-1991. https://doi.org/10.1038/sj.gt.3302103

Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. / van Beusechem, V. W.; Mastenbroek, D. C J; van den Doel, P. B.; Lamfers, M. L M; Grill, J.; Würdinger, T.; Haisma, H. J.; Pinedo, H. M.; Gerritsen, W. R.

In: Gene Therapy, Vol. 10, No. 23, 11.2003, p. 1982-1991.

Research output: Contribution to journalArticle

van Beusechem, VW, Mastenbroek, DCJ, van den Doel, PB, Lamfers, MLM, Grill, J, Würdinger, T, Haisma, HJ, Pinedo, HM & Gerritsen, WR 2003, 'Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors', Gene Therapy, vol. 10, no. 23, pp. 1982-1991. https://doi.org/10.1038/sj.gt.3302103
van Beusechem VW, Mastenbroek DCJ, van den Doel PB, Lamfers MLM, Grill J, Würdinger T et al. Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. Gene Therapy. 2003 Nov;10(23):1982-1991. https://doi.org/10.1038/sj.gt.3302103
van Beusechem, V. W. ; Mastenbroek, D. C J ; van den Doel, P. B. ; Lamfers, M. L M ; Grill, J. ; Würdinger, T. ; Haisma, H. J. ; Pinedo, H. M. ; Gerritsen, W. R. / Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. In: Gene Therapy. 2003 ; Vol. 10, No. 23. pp. 1982-1991.
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