Complement-Dependent Tumor Cell Lysis Triggered by Combinations of Epidermal Growth Factor Receptor Antibodies
Open Access
- 1 July 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (13), 4998-5003
- https://doi.org/10.1158/0008-5472.can-07-6226
Abstract
Therapeutic monoclonal antibodies against the epidermal growth factor receptor (EGFR) have advanced the treatment of colon and head and neck cancer, and show great promise for the development of treatments for other solid cancers. Antibodies against EGFR have been shown to act via inhibition of receptor signaling and induction of antibody-dependent cellular cytoxicity. However, complement-dependent cytotoxicity, which is considered one of the most powerful cell killing mechanisms of antibodies, seems inactive for such antibodies. Here, we show a remarkable synergy for EGFR antibodies. Combinations of antibodies against EGFR were identified, which resulted in potent complement activation via the classic pathway and effective lysis of tumor cells. Studies on a large panel of antibodies indicated that the observed synergy is a general mechanism, which can be activated by combining human IgG1 antibodies recognizing different, nonoverlapping epitopes. Our findings show an unexpected quality of therapeutic EGFR antibodies, which may be exploited to develop novel and more effective treatments for solid cancers. [Cancer Res 2008;68(13):4998–5003]Keywords
Other Versions
This publication has 21 references indexed in Scilit:
- Matuzumab Binding to EGFR Prevents the Conformational Rearrangement Required for DimerizationCancer Cell, 2008
- Antibody cocktails: next-generation biopharmaceuticals with improved potencyTrends in Biotechnology, 2007
- FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent CetuximabJournal of Clinical Oncology, 2007
- Antibody‐dependent cellular cytotoxicity of cetuximab against tumor cells with wild‐type or mutant epidermal growth factor receptorCancer Science, 2007
- Targeting Tyrosine Kinases in Cancer: The Second WaveScience, 2006
- Production of target‐specific recombinant human polyclonal antibodies in mammalian cellsBiotechnology & Bioengineering, 2006
- Complement function in mAb-mediated cancer immunotherapyTrends in Immunology, 2004
- ComplementThe New England Journal of Medicine, 2001
- Antigen-specific human antibodies from mice comprising four distinct genetic modificationsNature, 1994
- Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies.The Journal of Experimental Medicine, 1987