Peptide mimotopes recognized by antibodies cetuximab and matuzumab induce a functionally equivalent anti-EGFR immune response.
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.
Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt am Main, Germany.
C
C
Hartmann
N
N
Müller
A
A
Blaukat
J
J
Koch
I
I
Benhar
W S
WS
Wels
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003429:Cross Reactions; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000276:immunology*; D017434:Protein Structure, Tertiary
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000939:Epitopes; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D066246:ErbB Receptors; C520777:matuzumab; D000068818:Cetuximab