Open AccessFc‐engineered EGF‐R antibodies mediate improved antibody‐dependent cellular cytotoxicity (ADCC) against KRAS ‐mutated tumor cells
Author(s) -
Schlaeth Martin,
Berger Sven,
Derer Stefanie,
Klausz Katja,
Lohse Stefan,
Dechant Michael,
Lazar Greg A.,
SchneiderMerck Tanja,
Peipp Matthias,
Valerius Thomas
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01505.x
Subject(s) - antibody dependent cell mediated cytotoxicity , kras , cetuximab , antibody , cancer research , epidermal growth factor receptor , biology , transfection , cancer cell , epidermal growth factor , receptor , microbiology and biotechnology , cell culture , chemistry , monoclonal antibody , immunology , cancer , colorectal cancer , biochemistry , genetics
Oncogenic mutations of the KRAS gene have emerged as a common mechanism of resistance against epidermal growth factor receptor (EGF‐R)‐directed tumor therapy. Mutated KRAS leads to ligand‐independent activation of signaling pathways downstream of EGF‐R. Thereby, direct effector mechanisms of EGF‐R antibodies, such as blockade of ligand binding and inhibition of signaling, are bypassed. Thus, a humanized variant of the approved EGF‐R antibody Cetuximab inhibited growth of wild‐type KRAS ‐expressing A431 cells, but did not inhibit KRAS ‐mutated A549 tumor cells. We then investigated whether killing of tumor cells harboring mutated KRAS can be improved by enhancing antibody‐dependent cellular cytotoxicity (ADCC). Protein‐ and glyco‐engineering of antibodies’ Fc region are established technologies to enhance ADCC by increasing antibodies’ affinity to activating Fcγ receptors. Thus, EGF‐R antibody variants with increased affinity for the natural killer (NK) cell‐expressed FcγRIIIa (CD16) were generated and analyzed. These variants triggered significantly enhanced mononuclear cell (MNC)‐mediated killing of KRAS ‐mutated tumor cells compared to wild‐type antibodies. Additionally, cells transfected with mutated KRAS were killed as effectively by ADCC as vector‐transfected control cells. Together, these data demonstrate that KRAS mutations are not sufficient to render tumor cells resistant to ADCC. Consequently Fc‐engineered EGF‐R antibodies may prove effective against KRAS ‐mutated tumors, which are not susceptible to signaling inhibition by EGF‐R antibodies. ( Cancer Sci 2010; 101: 1080–1088)