Abstract
Aberrant activation of the epidermal growth factor receptor (EGFR) has been found in human cancers of various origins, and has been implicated in cancer pathogenesis. The therapeutic anti-EGFR antibodies cetuximab and matuzumab inhibit both ligand-induced receptor activation and growth of EGFR-expressing tumor cells. The efficacy of such EGFR-targeted therapies may be further enhanced by induction of functionally equivalent endogenous antibody responses. Here we describe novel peptide sequences selected from random peptide libraries for binding to single-chain antibody fragments of cetuximab or matuzumab. Two of these peptides characterized by KTL and YPLG motifs are recognized equally well by cetuximab and matuzumab, although nonoverlapping epitopes were previously reported for these antibodies. Immunization of experimental animals with synthetic KTL- and YPLG-containing peptides led to induction of antibodies that cross-react with human EGFR, and prevent binding of natural EGFR ligands, ligand-induced receptor activation and tumor cell growth in a manner similar to cetuximab and matuzumab. Our findings show that these peptide mimotopes can induce anti-EGFR antibodies with antitumoral activity, which may have implications for EGFR-specific cancer immunotherapy.
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Acknowledgements
We thank Dr Jens Oliver Funk, Merck KGaA for support of this project; Thorsten Geyer, Georg-Speyer-Haus for preparing plasmid pIB-Tx-scFv(225); Dr John Mendelsohn, MD Anderson Cancer Center, Houston for monoclonal antibody cetuximab; Dr Nancy Hynes, Friedrich Miescher Institute, Basel for 15E anti-EGFR antibody; Christian Brendel, Georg-Speyer-Haus for help with CLSM experiments and Dr Stephen Hyland, Georg-Speyer-Haus and Dr Arne Sutter, Merck KGaA for helpful discussions. This work was supported in part by a grant from Merck KGaA.
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A Blaukat is an employee of Merck KGaA, manufacturer of the drugs matuzumab and cetuximab. The authors declare no other potential conflict of interest.
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Hartmann, C., Müller, N., Blaukat, A. et al. Peptide mimotopes recognized by antibodies cetuximab and matuzumab induce a functionally equivalent anti-EGFR immune response. Oncogene 29, 4517–4527 (2010). https://doi.org/10.1038/onc.2010.195
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DOI: https://doi.org/10.1038/onc.2010.195
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