Complement-dependent tumor cell lysis triggered by combinations of epidermal growth factor receptor antibodies.
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.
Dechant
Michael
M
Department of Nephrology and Hypertension, and Section of Stem Cell Transplantation and Immunotherapy, Christian-Albrechts-University, Kiel, Germany.
Weisner
Wencke
W
Berger
Sven
S
Peipp
Matthias
M
Beyer
Thomas
T
Schneider-Merck
Tanja
T
Lammerts van Bueren
Jeroen J
JJ
Bleeker
Wim K
WK
Parren
Paul W H I
PW
van de Winkel
Jan G J
JG
Valerius
Thomas
T
D000906:Antibodies / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000502:physiology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018938:Caco-2 Cells; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D000068818:Cetuximab; D003165:Complement System Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D018604:Epitope Mapping; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000008:administration & dosage; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D000077544:Panitumumab; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007070:Immunoglobulin A; D007140:Immunoglobulin Fab Fragments; D000077544:Panitumumab; D003165:Complement System Proteins; D066246:ErbB Receptors; C520777:matuzumab; D000068818:Cetuximab