TY - JOUR
T1 - DARPin-targeting of measles virus
T2 - Unique bispecificity, effective oncolysis, and enhanced safety
AU - Friedrich, Katrin
AU - Hanauer, Jan R.H.
AU - Prüfer, Steffen
AU - Münch, Robert C.
AU - Völker, Iris
AU - Filippis, Christodoulos
AU - Jost, Christian
AU - Hanschmann, Kay Martin
AU - Cattaneo, Roberto
AU - Peng, Kah Whye
AU - Plückthun, Andreas
AU - Buchholz, Christian J.
AU - Cichutek, Klaus
AU - Mühlebach, Michael D.
N1 - Funding Information:
We thank U Schneider for providing the PolII Rescue System for measles viruses, Y Yanagi for providing CHO-hSLAM and T Abel for plasmid pS-TFP635-W. We are indebted to A Geyer, M Selbert, and D Kreuz for excellent technical assistance and to R Marschalek for helpful comments. This work has been supported by a grant from the German Cancer Aid (109614) to M.D.M and the LOEWE Center for Cell and Gene Therapy Frankfurt funded by Hessisches Ministerium für Wissenschaft und Kunst (III L 4-518/17.004 (2010)) to C.J.B. This work was performed in Langen, Germany. A.P. is a shareholder of Molecular Partners A6, who are commercializing the DARPin technology.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
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U2 - 10.1038/mt.2013.16
DO - 10.1038/mt.2013.16
M3 - Article
C2 - 23380817
AN - SCOPUS:84878552115
SN - 1525-0016
VL - 21
SP - 849
EP - 859
JO - Molecular Therapy
JF - Molecular Therapy
IS - 4
ER -