Oncotarget

Research Papers:

Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells

Meike Hutt, Sina Fellermeier-Kopf, Oliver Seifert, Lisa C. Schmitt, Klaus Pfizenmaier and Roland E. Kontermann _

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Oncotarget. 2018; 9:11322-11335. https://doi.org/10.18632/oncotarget.24379

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Abstract

Meike Hutt1, Sina Fellermeier-Kopf1, Oliver Seifert1, Lisa C. Schmitt1, Klaus Pfizenmaier1,2 and Roland E. Kontermann1,2

1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart 70569, Germany

2Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart 70569, Germany

Correspondence to:

Roland E. Kontermann, email: roland.kontermann@izi.uni-stuttgart.de

Keywords: TRAIL; targeting; affinity; receptor expression; apoptosis

Received: December 14, 2017     Accepted: January 25, 2018     Published: January 31, 2018

ABSTRACT

Fusion proteins combining hexavalent TRAIL with antibody fragments allow for a targeted delivery and efficient apoptosis induction in tumor cells. Here, we analyzed scFv-Fc-scTRAIL molecules directed against EGFR, HER2, HER3, and EpCAM as well as an untargeted Fc-scTRAIL fusion protein for their potentials to induce cell death both in vitro and in a xenograft tumor model in vivo. The scFv-Fc-scTRAIL fusion protein directed against EGFR as well as the fusion protein directed against EpCAM showed targeting effects on the two tested colorectal carcinoma cell lines Colo205 and HCT116, while a fusion protein targeting HER3 was more effective than untargeted Fc-scTRAIL only on Colo205 cells. Interestingly, another anti-HER3 scFv-Fc-scTRAIL fusion protein exhibiting approximately 10-fold weaker antigen binding as well as the HER2-directed molecule were unable to increase cytotoxicity compared to Fc-scTRAIL. A comparison of EC50 values of cell death induction and antigen binding supports the assumption that high affinity antigen binding is one of the requirements for in vitro targeting effects. Furthermore, a minimal number of expressed target antigens might be required for increased cytotoxicity of targeted compared to non-targeted molecules. In a Colo205 s.c. xenograft tumor model, strongest antitumor activity was observed for the anti-HER3 scFv-Fc-scTRAIL fusion protein based on antibody 3-43, with complete tumor remissions after six twice-weekly injections. Surprisingly, a similar in vivo activity was also observed for untargeted Fc-scTRAIL in this tumor model, indicating that additional factors contribute to the potent efficacy of targeted as well as untargeted hexavalent Fc-scTRAIL fusion proteins in vivo.


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