Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibody-dependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage

Tanja Schneider-Merck, Jeroen J. Van Lammerts Bueren, Sven Berger, Kai Rossen, Patrick H.C. Van Berkel, Stefanie Derer, Thomas Beyer, Stefan Lohse, Wim K. Bleeker, Matthias Peipp, Paul W.H.I. Parren, Jan G.J. Van De Winkel, Thomas Valerius*, Michael Dechant

*Corresponding author for this work
154 Citations (Scopus)

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 FcγRIIa. Panitumumab-mediated ADCC was significantly affected by the functional FcγRIIa-R131H polymorphism and was induced more effectively by neutrophils from FcγRIIa-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.

Original languageEnglish
JournalJournal of Immunology
Volume184
Issue number1
Pages (from-to)512-520
Number of pages9
ISSN0022-1767
DOIs
Publication statusPublished - 01.01.2010

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

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