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Abstract
Background Cetuximab is a recombinant human/mouse chimeric epidermal growth factor receptor (EGFR) monoclonal antibody. Cetuximab mechanisms of action is based on disruption of EGFR signaling pathways as dominant mechanism and ADCC effect as a secondary one. The aims of this study were (1) to develop a model describing Cetuximab mechanism of action and effect on head and neck cancer cell lines observed in vitro with a purpose to integrate them in quantitative systems pharmacology (QSP) model of HNSCC and (2) to apply the in vitro model to study contributions of EGFR signaling disruption vs ADCC of Cetuximab for different E:T ratios.
Methods A model describing Cetuximab mechanism of action includes
Tumor and NK cells
Tumor cell proliferation and processes describing NK dependent and independent death
Immunological synapse formed by Tumor and NK cell
Binding of EGF to EGFR located at the surface of Tumor cells and disruption of the signaling complex with Cetuximab
Formation of trimer between EGFR located on tumor cell, cetuximab and Fcg3A receptor on NK cells
Direct effect of cetuximab on tumor cell proliferation via decrease in signaling complexes EGF-EGFR
ADCC effect of cetuximab on Tumor cell death via stimulation of NK-mediated cytotoxicity with trimer EGFR-Cetuximab- FcgR3A
The model was calibrated against following datasets:
EGF effect on cell culture growth: UM-SCC-3 1
Time course of cell culture growth treated with Cetuximab, NK, Cetuximab +NK for 48 hours: SCC22b 2
Dependence of ADCC on Cetuximab dose treated with Cetuximab +NK for 4 hours: Ho-1-u-1 3
Results Validation of the model was performed to confirm its predictive power. Datasets describing survival, cytotoxicity and ADCC as functions of E:T ratio and EGFR expression level were successfully reproduced (see example in figure 1). The model was applied to analyze contribution of signaling/direct effect of Cetuximab and ADCC for different E:T ratios. We have found that contribution of ADCC is observed starting from E:T = 1:100. Model predicts that ADCC effect contribution is comparable with that of signaling/direct effect of cetuximab in following range E:T = 1:2 – 1:1. Starting from E:T = 1:1 ADCC contribution exceeds that of signaling/direct effect.
Conclusions The developed model can adequately describe the effects of Cetuximab observed in in vitro experiments. The model was applied to estimate contribution of ADCC and direct effect of Cetuximab at various E:T ratios and EGFR expression levels.
References
Makarova G, Bette M, Schmidt A, Jacob R, Cai C, Rodepeter F, Betz T, Sitterberg J, Bakowsky U, Moll R, Neff A, Sesterhenn A, Teymoortash A, Ocker M, Werner JA, Mandic R. Epidermal growth factor-induced modulation of cytokeratin expression levels influences the morphological phenotype of head and neck squamous cell carcinoma cells. Cell Tissue Res. 2013;351(1):59–72.
Baysal H, De Pauw I, Zaryouh H, De Waele J, Peeters M, Pauwels P, Vermorken JB, Smits E, Lardon F, Jacobs J, Wouters A. Cetuximab-induced natural killer cell cytotoxicity in head and neck squamous cell carcinoma cell lines: investigation of the role of cetuximab sensitivity and HPV status. Br J Cancer. 2020;123(5):752–761.
Nakamura H, Tamaki S, Yagyuu T, Yamakawa N, Hatake K, Kirita T. Relationship Between EGFR Expression in Oral Cancer Cell Lines and Cetuximab Antibody-dependent Cell-mediated Cytotoxicity. Anticancer Res. 2019;39(3):1275–1282.
Correspondence between experimental data (dots) [3] and simulations (lines) describing cytotoxicity of NK cells with (magenta) and without (blue) 10 ug/ml Cetuximab. Target cells (Ho-1-u-1 cell line) were incubated with NK and Cetuximab for 4 hours and Cytotoxicity was plotted as function of effector:target ratio
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