title: DARPin-targeting of measles virus: unique bispecificity, effective oncolysis, and enhanced safety.
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.
authors: Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany.
authors: Katrin
authors: K
authors: Friedrich
authors: Jan Rh
authors: JR
authors: Hanauer
authors: Steffen
authors: S
authors: Prüfer
authors: Robert C
authors: RC
authors: Münch
authors: Iris
authors: I
authors: Völker
authors: Christodoulos
authors: C
authors: Filippis
authors: Christian
authors: C
authors: Jost
authors: Kay-Martin
authors: KM
authors: Hanschmann
authors: Roberto
authors: R
authors: Cattaneo
authors: Kah-Whye
authors: KW
authors: Peng
authors: Andreas
authors: A
authors: Plückthun
authors: Christian J
authors: CJ
authors: Buchholz
authors: Klaus
authors: K
authors: Cichutek
authors: Michael D
authors: MD
authors: Mühlebach
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*
references: MMWR Morb Mortal Wkly Rep. 1996 Jul 19;45(28):603-6
references: 8676852
references: Nat Biotechnol. 2012 Jul 10;30(7):658-70
references: 22781695
references: Curr Pharm Biotechnol. 2012 Jul;13(9):1732-41
references: 21740361
references: Lancet. 1971 Jul 10;2(7715):105-6
references: 4103972
references: Cancer Res. 2010 Feb 1;70(3):875-82
references: 20103634
references: Curr Opin Biotechnol. 2011 Dec;22(6):849-57
references: 21715155
references: PLoS Pathog. 2011 Aug;7(8):e1002240
references: 21901103
references: Mol Ther. 2011 Apr;19(4):686-93
references: 21224833
references: Cancer Res. 2010 Oct 1;70(19):7620-9
references: 20858718
references: Nat Rev Clin Oncol. 2011 Nov 29;9(1):16-32
references: 22124364
references: Nat Biotechnol. 2005 Feb;23(2):209-14
references: 15685166
references: J Mol Biol. 2009 Oct 30;393(3):598-607
references: 19683003
references: Nature. 2000 Aug 24;406(6798):893-7
references: 10972291
references: Hum Gene Ther. 2008 Jul;19(7):690-8
references: 18576918
references: J Infect Dis. 2005 Nov 15;192(10):1686-93
references: 16235165
references: J Natl Cancer Inst. 2010 May 5;102(9):590-5
references: 20421567
references: J Virol. 2011 Jan;85(1):348-56
references: 20980517
references: J Virol. 2001 Mar;75(5):2087-96
references: 11160713
references: Nat Rev Microbiol. 2008 Jul;6(7):529-40
references: 18552863
references: Int J Cancer. 2012 Aug 15;131(4):844-54
references: 21935923
references: J Virol. 2007 Dec;81(23):13149-57
references: 17804513
references: J Virol. 1993 Oct;67(10):6025-32
references: 8371352
references: Cancer Res. 2004 Jul 15;64(14):4919-26
references: 15256464
references: Nat Med. 2012 Jan 22;18(2):221-3
references: 22270724
references: J Mol Biol. 2001 Feb 2;305(5):989-1010
references: 11162109
references: Mol Cancer Ther. 2009 Sep;8(9):2674-83
references: 19723880
references: Nat Rev Cancer. 2009 Feb;9(2):143; author reply 143
references: 19132011
references: Blood. 2003 Apr 1;101(7):2557-62
references: 12433686
references: Hum Gene Ther. 2012 May;23(5):484-91
references: 22171635
references: J Biol Chem. 2005 May 20;280(20):19543-50
references: 15784625
references: Nat Rev Cancer. 2012 Jul 12;12(8):553-63
references: 22785351
references: Cancer Res. 2010 Feb 15;70(4):1595-605
references: 20124480
references: J Virol. 1998 Sep;72(9):7420-7
references: 9696838
references: Hum Pathol. 2004 Jan;35(1):122-8
references: 14745734
references: Oncogene. 2002 Jun 20;21(27):4212-9
references: 12082608
references: J Mol Biol. 2011 Nov 4;413(4):826-43
references: 21963989
references: J Virol. 2006 Jun;80(12):5708-15
references: 16731909
references: Exp Hematol. 2006 Jun;34(6):713-20
references: 16728275
references: Cell. 1993 Oct 22;75(2):295-305
references: 8402913
references: Nat Biotechnol. 2004 May;22(5):575-82
references: 15097997
references: J Mol Biol. 2011 Jan 14;405(2):410-26
references: 21056576
references: J Immunol Methods. 2001 Feb 1;248(1-2):47-66
references: 11223068
references: Mol Ther. 2008 Aug;16(8):1427-36
references: 18578012
references: Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14216-21
references: 15377791
references: Cancer Res. 2007 Nov 15;67(22):10939-47
references: 18006839
references: Natl Vital Stat Rep. 2009 Apr 17;57(14):1-134
references: 19788058
references: Nature. 2011 Nov 02;480(7378):530-3
references: 22048310
references: J Mol Biol. 2008 Oct 24;382(5):1211-27
references: 18706916
references: Hum Gene Ther. 2012 Oct;23(10):1054-64
references: 22734672