PT  - JOURNAL ARTICLE
AU  - Demin, Oleg
AU  - Smirnov, Sergey
AU  - Diakonova, Alexandra
AU  - Roskoshnaia, Anna
AU  - Bajaj, Gaurav
AU  - Adams, Homer
AU  - Gupta, Manish
AU  - Thalhauser, Craig
TI  - 1280 Modeling of direct (EGFR- based) and ADCC cytotoxic effect of Cetuximab on the basis of literature available <em>in vitro</em> data
AID  - 10.1136/jitc-2023-SITC2023.1280
DP  - 2023 Nov 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - A1420--A1420
VI  - 11
IP  - Suppl 1
4099  - http://jitc.bmj.com/content/11/Suppl_1/A1420.short
4100  - http://jitc.bmj.com/content/11/Suppl_1/A1420.full
SO  - J Immunother Cancer2023 Nov 01; 11
AB  - 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 includesTumor and NK cellsTumor cell proliferation and processes describing NK dependent and independent deathImmunological synapse formed by Tumor and NK cellBinding of EGF to EGFR located at the surface of Tumor cells and disruption of the signaling complex with CetuximabFormation of trimer between EGFR located on tumor cell, cetuximab and Fcg3A receptor on NK cellsDirect effect of cetuximab on tumor cell proliferation via decrease in signaling complexes EGF-EGFRADCC effect of cetuximab on Tumor cell death via stimulation of NK-mediated cytotoxicity with trimer EGFR-Cetuximab- FcgR3AThe 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.ReferencesMakarova 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.Abstract 1280 Figure 1 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