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.
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.
Schneider-Merck
Tanja
T
Department of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany.
Lammerts van Bueren
Jeroen J
JJ
Berger
Sven
S
Rossen
Kai
K
van Berkel
Patrick H C
PH
Derer
Stefanie
S
Beyer
Thomas
T
Lohse
Stefan
S
Bleeker
Wim K
WK
Peipp
Matthias
M
Parren
Paul W H I
PW
van de Winkel
Jan G J
JG
Valerius
Thomas
T
Dechant
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D019070:Cell Lineage; D066246:ErbB Receptors / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D000077544:Panitumumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D000077544:Panitumumab; C546618:zalutumumab; D066246:ErbB Receptors