title: IgG1 anti-epidermal growth factor receptor antibodies induce CD8-dependent antitumor activity.
abstract: 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.
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg University, 55131, Mainz, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kubach
authors.forename: Mario
authors.initials: M
authors.lastname: Hubo
authors.forename: Christiane
authors.initials: C
authors.lastname: Amendt
authors.forename: Christopher
authors.initials: C
authors.lastname: Stroh
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D058851:GPI-Linked Proteins / Q000378:metabolism; D006086:Graft vs Host Disease / Q000188:drug therapy; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D019409:Interleukin-15 / Q000502:physiology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017452:Receptors, IgG / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D007074:Immunoglobulin G; D019409:Interleukin-15; D017452:Receptors, IgG; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: ADCC; anti-EGFR antibodies; humanized mice