Anti-(epidermal growth factor) receptor monoclonal antibodies for the induction of antibody-dependent cell-mediated cytotoxicity against squamous cell carcinoma lines of the head and neck |
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Authors: | Henning Bier Thomas Hoffmann Inge Haas Anke van Lierop |
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Institution: | (1) Department of Otorhinolaryngology/Head and Neck Surgery, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany Tel.: +49 211 811 7570; Fax: +49 211 811 8880, DE |
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Abstract: | Squamous cell carcinomas of the head and neck (SCCHN) frequently display high levels of the epidermal growth factor receptor
(EGFR). Since EGFR is expressed on the cell surface it may form a suitable target for anticancer therapy with anti-receptor
monoclonal antibodies (mAb). Besides the interference with receptor/ligand interactions, binding of mAb to EGFR leads to immunoglobulin-coated
tumour cells that may induce or enhance non-specific immune effector mechanisms like antibody-dependent cell-mediated cytotoxicity
(ADCC). In established cell lines of SCCHN (UM-SCC 11B, 14C, 22B, and 8029 NA) we investigated the antitumour activity of
allogeneic peripheral blood mononuclear cells (PBMC) in combination with rat (ICR 62), mouse (EMD 55900), and humanized (EMD
72000) anti-EGFR mAb. In addition, autologous PBMC were available for tumour line UD-SCC 4. The EGFR protein content of the
tumour cell lines ranged between 170 fmol/mg protein and 8100 fmol/mg protein, and MCF-7 cells served as receptor-negative
controls. PBMC activity against SCCHN targets was determined in 96-well microtitre-plate monolayer cultures by the colorimetric
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after coincubation for 4 h, 24 h and 72 h at effector target
ratios of 1:1, 5:1, 10:1 and 20:1. PBMC subpopulations were obtained by macrophage depletion (plastic adherence) or natural
killer (NK) cell enrichment (magnetic bead negative selection). Prolonged time of exposure and increased effector:target ratios
revealed marked antitumour activity of PBMC alone. This non-specific immune destruction was enhanced considerably by humanized
and rat, but not mouse anti-EGFR mAb. Increased EGFR protein in tumour cells partly correlated with an intensification of
ADCC but was accompanied by decreased primary PBMC cytotoxicity. The utilization of PBMC subpopulations suggested a mainly
NK-cell-mediated ADCC, which appeared to benefit directly or indirectly, e.g. via the secretion of cytokines, from other PBMC
components. In conclusion, humanized (EMD 72000) and rat (ICR 62) anti-EGFR mAb were able to generate strong antitumour ADCC
in target monolayers of SCCHN.
Received: 5 December 1997 / Accepted: 15 January 1998 |
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Keywords: | Head and neck carcinoma monolayer Epidermal growth factor receptor Monoclonal antibodies Antibody-dependent cell-mediated cytotoxicity |
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