Dual Mode of Action of a Human Anti-Epidermal Growth Factor Receptor Monoclonal Antibody for Cancer Therapy
Open Access
- 1 October 2004
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 173 (7), 4699-4707
- https://doi.org/10.4049/jimmunol.173.7.4699
Abstract
Epidermal growth factor receptor (EGF-R) overexpression is common in a large number of solid tumors and represents a negative prognostic indicator. Overexpression of EGF-R is strongly tumor associated, and this tyrosine kinase type receptor is considered an attractive target for Ab therapy. In this study, we describe the evaluation of mAb 2F8, a high avidity human mAb (IgG1κ) directed against EGF-R, developed using human Ig transgenic mice. mAb 2F8 effectively blocked binding of EGF and TGF-α to the EGF-R. At saturating concentrations, 2F8 completely blocked EGF-R signaling and inhibited the in vitro proliferation of EGF-R-overexpressing A431 cells. At much lower concentrations, associated with low receptor occupancy, 2F8 induced efficient Ab-dependent cell-mediated cytotoxicity (ADCC) in vitro. In vivo studies showed potent antitumor effects in models with A431 tumor xenografts in athymic mice. Ex vivo analysis of the EGF-R status in tumor xenografts in 2F8-treated mice revealed that there are two therapeutic mechanisms. First, blocking of EGF-R signaling, which is most effective at complete receptor saturation and therefore requires a relatively high Ab dose. Second, at very low 2F8 receptor occupancy, we observed potent antitumor effects in mice, which are likely based on the engagement of immune effector mechanisms, in particular ADCC. Taken together, our findings indicate that ADCC represents an important effector mechanism of this Ab, which is effective at relatively low dose.Keywords
This publication has 28 references indexed in Scilit:
- ErbB-targeted therapeutic approaches in human cancerExperimental Cell Research, 2003
- Trafficking of the ErbB receptors and its influence on signalingExperimental Cell Research, 2003
- Generating high-avidity human Mabs in miceNature Biotechnology, 1996
- Receptor blockade with monoclomal antibodies as anti-cancer therapyPharmacology & Therapeutics, 1994
- Antigen-specific human antibodies from mice comprising four distinct genetic modificationsNature, 1994
- Antitumor Effects of Doxorubicin in Combination With Anti-epidermal Growth Factor Receptor Monoclonal AntibodiesJNCI Journal of the National Cancer Institute, 1993
- IMPORTANCE OF ANTIGEN SPECIFICITY FOR COMPLEMENT‐MEDIATED LYSIS BY MONOCLONAL ANTIBODIESEuropean Journal of Immunology, 1988
- Structure and Function of Human and Murine Receptors for IgGAnnual Review of Immunology, 1988
- Emergence of Idiotype Variants during Treatment of B-Cell Lymphoma with Anti-Idiotype AntibodiesThe New England Journal of Medicine, 1985
- Treatment of B-Cell Lymphoma with Monoclonal Anti-Idiotype AntibodyThe New England Journal of Medicine, 1982