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In vitro effects and ex vivo binding of an EGFR-specific immunotoxin on rhabdomyosarcoma cells

 
: Niesen, J.; Brehm, H.; Stein, C.; Berges, N.; Pardo, A.; Fischer, R.; Haaf, A. ten; Gattenlöhner, S.; Tur, M.K.; Barth, S.

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Journal of cancer research and clinical oncology 141 (2014), No.6, pp.1049-1061
ISSN: 0171-5216 (Print)
ISSN: 0084-5353
ISSN: 0943-9382
ISSN: 1432-1335 (Online)
English
Journal Article
Fraunhofer IME ()

Abstract
PURPOSE:
Rhabdomyosarcoma (RMS) is a rare and aggressive soft tissue sarcoma with limited treatment options and a high failure rate during standard therapy. New therapeutic strategies based on targeted immunotherapy are therefore much in demand. The epidermal growth factor receptor (EGFR) has all the characteristics of an ideal target. It is overexpressed in up to 80 % of embryonal RMS and up to 50 % of alveolar RMS tumors. We therefore tested the activity of the EGFR-specific recombinant immunotoxin (IT) 425(scFv)-ETA' against EGFR(+) RMS cells in vitro and ex vivo.
METHODS:
We tested the specific binding and internalization behavior of 425(scFv)-ETA' in RMS cell lines in vitro by flow cytometry, compared to the corresponding imaging probe 425(scFv)-SNAP monitored by live cell imaging. The cytotoxic activity of 425(scFv)-ETA' was tested using cell viability and apoptosis assays. Specific binding of the IT was confirmed on formalin-fixed paraffin-embedded tissue samples from two RMS patients.
RESULTS:
We confirmed the specific binding of 425(scFv)-ETA' to RMS cells in vitro and ex vivo. Both the IT and the corresponding imaging probe were rapidly internalized. The IT killed EGFR(+) RMS cells in a dose-dependent manner, while showing no effect against control cells. It showed specific apoptotic activity against one selected RMS cell line.
CONCLUSIONS:
This is the first study showing the promising therapeutic potential of a recombinant, EGFR-targeting, ETA'-based IT on RMS cells. We confirmed the selective killing with IC50 values of up to 50 pM, and immunohistochemical staining confirmed the specific ex vivo binding to primary RMS material.

: http://publica.fraunhofer.de/documents/N-356307.html