DARPin-targeting of measles virus: Unique bispecificity, effective oncolysis, and enhanced safety

Katrin Friedrich, Jan R.H. Hanauer, Steffen Prüfer, Robert C. Münch, Iris Völker, Christodoulos Filippis, Christian Jost, Kay Martin Hanschmann, Roberto Cattaneo, Kah Whye Peng, Andreas Plückthun, Christian J. Buchholz, Klaus Cichutek, Michael D. Mühlebach

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Many naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. In addition, specific targeting of cancer cells can be achieved at the virus entry level. We optimized retargeting of cell entry by elongating the measles virus attachment protein with designed ankyrin repeat proteins (DARPins), while simultaneously ablating entry through the natural receptors. DARPin-targeted viruses were strongly attenuated in off-target tissue, thereby enhancing safety, but completely eliminated tumor xenografts. Taking advantage of the unique properties of DARPins of being fused without generating folding problems, we generated a virus simultaneous targeting two different tumor markers. The bispecific virus retained the original oncolytic efficacy, while providing proof of concept for a strategy to counteract issues of resistance development. Thus, DARPin-targeting opens new prospects for the development of personalized, targeted therapeutics.

Original languageEnglish (US)
Pages (from-to)849-859
Number of pages11
JournalMolecular Therapy
Volume21
Issue number4
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Friedrich, K., Hanauer, J. R. H., Prüfer, S., Münch, R. C., Völker, I., Filippis, C., Jost, C., Hanschmann, K. M., Cattaneo, R., Peng, K. W., Plückthun, A., Buchholz, C. J., Cichutek, K., & Mühlebach, M. D. (2013). DARPin-targeting of measles virus: Unique bispecificity, effective oncolysis, and enhanced safety. Molecular Therapy, 21(4), 849-859. https://doi.org/10.1038/mt.2013.16