Anti-EGFR
monoclonal antibodies (mAb) like
Cetuximab are commonly used for treatment of EGFR+ solid
tumors mainly by exerting their
therapeutic effect through inhibition of signal transduction. Additionally,
IgG1 is a potent mediator of antibody-dependent cytotoxicity (ADCC). In case of the
IgG1,
Cetuximab induction of ADCC in vivo is controversially discussed. In our study, we investigated the efficiency of
Cetuximab-mediated ADCC in a humanized mouse
tumor model in vivo and analyzed the contribution of immunologic processes toward antitumor activity. Therefore, we used immunodeficient NOD/Scid mice transgenic for human
MHC class I molecule HLA-A2 and adoptively transferred human HLA-A2+ PBMC after engraftment of human epidermoid cell
carcinoma A431. Here, we show that high doses of anti-EGFR mAb induced strong
tumor regression independent of the immune system. However,
tumor regression by low doses of anti-EGFR mAb treatment was ADCC dependent and mediated by
tumor infiltrating CD8+ T effector cells. This novel mechanism of ADCC conducted by CD8+ T effector cells was restricted to
IgG1 anti-EGFR mAb, dependent of binding to CD16 on T cells and could be inhibited after EGFR blockade on
tumor cells. Furthermore, CD8+ T effector cell-mediated ADCC was enhanced in the presence of
IL-15 and strongly improved after glycosylation of anti-EGFR mAb indicating the potential of glycoengineered therapeutic mAb as efficient
biologicals in
cancer therapy.