Abstract
Ab-dependent cellular cytotoxicity (ADCC) is usually considered an important mechanism of action for immunotherapy with human IgG1 but not IgG2 Abs. The epidermal growth factor receptor (EGF-R) Ab panitumumab represents the only human IgG2 Ab approved for immunotherapy and inhibition of EGF-R signaling has been described as its principal mechanism of action. In this study, we investigated effector mechanisms of panitumumab compared with zalutumumab, an EGF-R Ab of the human IgG1 isotype. Notably, panitumumab was as effective as zalutumumab in recruiting ADCC by myeloid effector cells (i.e., neutrophils and monocytes) in contrast to NK cell-mediated ADCC, which was only induced by the IgG1 Ab. Neutrophil-mediated tumor cell killing could be stimulated by myeloid growth factors and was triggered via FcgammaRIIa. Panitumumab-mediated ADCC was significantly affected by the functional FcgammaRIIa-R131H polymorphism and was induced more effectively by neutrophils from FcgammaRIIa-131H homozygous donors than from -131R individuals. This polymorphism did not affect neutrophil ADCC induced by the IgG1 Ab zalutumumab. The in vivo activity of both Abs was assessed in two animal models: a high-dose model, in which signaling inhibition is a dominant mechanism of action, and a low-dose model, in which effector cell recruitment plays a prominent role. Zalutumumab was more effective than panitumumab in the high-dose model, reflecting its stronger ability to induce EGF-R downmodulation and growth inhibition. In the low-dose model, zalutumumab and panitumumab similarly prevented tumor growth. Thus, our results identify myeloid cell-mediated ADCC as a potent and additional mechanism of action for EGF-R-directed immunotherapy.
Highlights
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Zalutumumab proved to be more potent than panitumumab with respect to downmodulation of epidermal growth factor receptor (EGF-R) (Fig. 1C)
With unfractionated whole blood as effector source, both Abs induced similar killing levels (Fig. 2E; zalutumumab: EC50: 0.064 mg/ml; 95% confidence interval (CI), 0.006–0.745 mg/ml; top plateau 38.1% 6 8.3%; panitumumab: EC50: 0.068 mg/ml; 95% CI, 0.020–0.226 mg/ml; top plateau 26.8% 6 3.3%; n = 5), demonstrating that mononuclear cell (MNC) and polymorphonuclear cell (PMN) contribute to the Ab-dependent cellular cytotoxicity (ADCC) activity in human blood
Summary
Novel EGF-R Abs, such as the human IgG1 Ab zalutumumab, for which mononuclear cell (MNC)induced ADCC has been described as an important mechanism of action, are being actively investigated [19,20,21]. With unfractionated whole blood as effector source, both Abs induced similar killing levels (Fig. 2E; zalutumumab: EC50: 0.064 mg/ml; 95% CI, 0.006–0.745 mg/ml; top plateau 38.1% 6 8.3%; panitumumab: EC50: 0.068 mg/ml; 95% CI, 0.020–0.226 mg/ml; top plateau 26.8% 6 3.3%; n = 5), demonstrating that MNCs and PMNs contribute to the ADCC activity in human blood.
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