Abstract
Single-chain formats of TNF-related apoptosis inducing ligand (scTRAIL) can serve as effector components of tumour-associated antigen-targeted as well as non-targeted fusion proteins, being characterized by high tumour cell-specific induction of apoptosis through death receptor activation. We studied the suitability of immunoglobulin G as a scaffold for oligovalent and bispecific TRAIL fusion proteins. Thus, we developed novel targeted hexa- and dodecavalent IgG-scTRAIL molecules by fusing scTRAIL to the C-terminus of either light (LC-scTRAIL) or heavy immunoglobulin chain (HC-scTRAIL), or to both ends (LC/HC-scTRAIL) of the anti-EGFR IgG antibody hu225. The binding specificity to EGFR and death receptors was retained in all IgG-scTRAIL formats and translated into high antigen-specific bioactivity on EGFR-positive Colo205, HCT116 and WM1366 tumour cell lines, with or without sensitization to apoptosis by bortezomib. In vivo, therapeutic potential was assessed for one of the targeted variants, HC-scTRAIL, compared to the non-targeted Fc-scTRAIL. Both molecules showed a significant reduction of tumour volume and synergism with a Smac mimetic in a Colo205 xenograft tumour model. The IgG-scTRAIL format allows directing a defined, h...Continue Reading
References
Aug 24, 1999·European Journal of Immunology·K L ArmourL M Williamson
Aug 9, 2001·Oncogene·H WajantK Pfizenmaier
Apr 12, 2002·Oncogene·Simone FuldaKlaus-Michael Debatin
May 6, 2004·Cancer Research·Jordan M CumminsFred Bunz
Sep 21, 2007·Cancer Biology & Therapy·Robyn T SussmanWafik S El-Deiry
Jun 5, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Anja Krippner-HeidenreichPeter Scheurich
Nov 4, 2008·Oncogene·B ThayaparasinghamD Kulms
Oct 12, 2010·MAbs·Kirstin A ZettlitzRoland Kontermann
Jan 11, 2011·Cancer Letters·Marco de BruynWijnand Helfrich
Jan 18, 2011·Cancer Letters·Harald WajantKlaus Pfizenmaier
Jan 1, 2008·CSH Protocols·Roseanne TomYves Durocher
Mar 3, 2011·Cell Death & Disease·B SchneiderJ Gerspach
Jul 19, 2011·Recent Patents on Anti-cancer Drug Discovery·Jeannette GerspachHarald Wajant
Apr 13, 2012·Cell Death & Disease·M SiegemundK Pfizenmaier
Sep 4, 2012·International Journal of Molecular Sciences·Carmine StolfiGiovanni Monteleone
Oct 5, 2013·Molecular Cancer Therapeutics·Oliver SeifertRoland E Kontermann
Oct 9, 2013·Molecular Cancer Therapeutics·Christian GieffersOliver Hill
Feb 12, 2014·Methods in Molecular Biology·Martin SiegemundRoland E Kontermann
Jun 10, 2014·Oncogene·Mark H TuthillHenning Walczak
Sep 10, 2014·PloS One·Yvonne MöllerMonilola A Olayioye
Mar 5, 2016·Cell Death and Differentiation·D de MiguelL Martinez-Lostao
Apr 12, 2016·MAbs·Martin SiegemundRoland E Kontermann
Jul 29, 2016·Oncoimmunology·Xiuhong PiaoAtsushi Muraguchi
Dec 29, 2016·Cell Death Discovery·Karianne G FletenBirgit Engesæter
Feb 19, 2017·Molecular Cell·Torsten HartwigHenning Walczak
Jun 7, 2017·Oncology Reviews·George E NaoumWaleed O Arafat
Sep 15, 2017·Molecular Cancer Therapeutics·Meike HuttRoland E Kontermann
Mar 16, 2018·Oncotarget·Meike HuttRoland E Kontermann
Citations
Nov 13, 2018·NPJ Systems Biology and Applications·Greta Del MistroDagmar Kulms
Jul 10, 2019·Cancers·Harald Wajant
Jan 18, 2019·Oncotarget·Elena BrinJames Thomson
Jun 13, 2020·Frontiers in Pharmacology·Franziska HartungLuis A Pardo
Jun 13, 2020·Frontiers in Cell and Developmental Biology·Roman FischerKlaus Pfizenmaier
Jun 20, 2019·Molecular Cancer Therapeutics·Barbara ZiffelsDario Neri
May 21, 2020·Molecular Cancer Therapeutics·Alexander RauRoland E Kontermann
Apr 3, 2021·Science·Robby DivineDavid Baker
Feb 17, 2020·Antibody Therapeutics·Siwei NieJijie Gu
Jul 3, 2021·Journal of Clinical Medicine·Dorothee WinterbergDenis Martin Schewe
Nov 12, 2021·Frontiers in Pharmacology·Martin SiegemundChristine Rothe
Jan 14, 2022·Cell Death & Disease·Greta Del MistroDagmar Kulms