Fc-engineered EGF-R antibodies mediate improved antibody-dependent cellular cytotoxicity (ADCC) against KRAS-mutated tumor cells

Martin Schlaeth, Sven Berger, Stefanie Derer*, Katja Klausz, Stefan Lohse, Michael Dechant, Greg A. Lazar, Tanja Schneider-Merck, Matthias Peipp, Thomas Valerius

*Corresponding author for this work
32 Citations (Scopus)


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.

Original languageEnglish
JournalCancer Science
Issue number5
Pages (from-to)1080-1088
Number of pages9
Publication statusPublished - 05.2010

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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