Pharmacological and immunological characteristics of the therapeutic anti-EGFR antibodies cetuximab, panitumumab, and nimotuzumab.

Abstract

e13025 Background: Therapeutic antibodies can affect tumor cells by functionally interfering with the target and/or by employing immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). The scope of this study was to analyze the clinically used anti-EGFR therapeutic antibodies cetuximab, panitumumab, and nimotuzumab with regard to both modes of action: interference with EGFR function and ADCC activity. Methods: EGFR binding and inhibition of EGFR signal transduction were characterized in A431, A549, and HCT116 tumor cell lines. The ability to kill these tumor cells via ADCC was analyzed in ex vivo assays using human immune effector cells isolated from blood. Results: In cellular assays using A431, A549, and HCT116 cells cetuximab and panitumumab showed similar EGFR binding affinities (Kd values for binding to A431 cells of cetuximab and panitumumab: 5 nM and 4 nM, respectively) while nimotuzumab bound to EGFR with lower affinity (Kd for binding to A431 cells: ∼ 90 nM). The EGFR binding behavior correlated with the ability to inhibit EGFR signal transduction (phospho-EGFR, phospho-ERK1/2, phospho-Akt, phospho- STAT3) as well as inhibition of VEGF and IL-8 production. Using peripheral blood mononuclear cells (PBMCs) as effector cells, cetuximab mediated a marked, dose-dependent ADCC response in all three cell lines. Nimotuzumab displayed weak ADCC activity, while no or only marginal ADCC was observed with panitumumab. NK cells were the main effector cells of the PBMC fraction. With all three antibodies no ADCC activity was seen when polymymorphonuclear leukocytes were used as effector cells. Conclusions: Although cetuximab, panitumumab, and nimotuzumab are all clinically applied therapeutic antibodies directed against the EGFR, the results of this investigation suggest that different modes of action may contribute to the clinical efficacy of the antibodies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration EMD Serono, Merck KGaA, Merck Serono