Functional dissection of the epidermal growth factor receptor epitopes targeted by panitumumab and cetuximab.
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Functional dissection of the epidermal growth factor receptor epitopes targeted by panitumumab and cetuximab. / Voigt, Mareike; Braig, Friederike; Goethel, Markus; Schulte, Alexander; Lamszus, Katrin; Bokemeyer, Carsten; Binder, Mascha.
In: NEOPLASIA, Vol. 14, No. 11, 11, 2012, p. 1023-1031.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Functional dissection of the epidermal growth factor receptor epitopes targeted by panitumumab and cetuximab.
AU - Voigt, Mareike
AU - Braig, Friederike
AU - Goethel, Markus
AU - Schulte, Alexander
AU - Lamszus, Katrin
AU - Bokemeyer, Carsten
AU - Binder, Mascha
PY - 2012
Y1 - 2012
N2 - Cetuximab and panitumumab, two antibodies targeting the extracellular domain of the epidermal growth factor receptor (EGFR), are of major clinical importance particularly in the treatment of metastatic colorectal cancer. As patients may acquire resistance-mediating mutations within the extracellular EGFR domain, functional dissection of the exact binding sites of EGFR targeting antibodies may help predict treatment responses. We therefore assessed the epitope recognition of panitumumab by screening phage-displayed random cyclic 7mer and linear 12mer peptide libraries on this antibody. Phage screenings revealed two strong, potentially epitope-mimicking consensus motifs targeted by panitumumab. A computational approach was used to map the sequences back to the potential epitope region on domain III of EGFR. The presumed epitope regions (386)WPEXRT(391) and a biochemically similar though discontinuous region P349-F352-D355 on a neighboring loop of domain III could be confirmed as part of the functionally relevant binding site of panitumumab by site-directed mutational analysis. To more accurately differentiate the panitumumab epitope from the previously characterized cetuximab epitope, binding studies were performed on a broad range of additional mutants. Taken together, this analysis revealed two large, partially overlapping functional epitopes consisting of 17 critical amino acid positions. Four of these positions were selectively targeted by cetuximab (I467, S468, Q408, and H409), whereas another four were selectively recognized by panitumumab (W386, E388, R390, and T391). In view of the clinical significance of extracellular domain mutations, our data may help guide treatment decisions in selected patients receiving EGFR-targeted therapies.
AB - Cetuximab and panitumumab, two antibodies targeting the extracellular domain of the epidermal growth factor receptor (EGFR), are of major clinical importance particularly in the treatment of metastatic colorectal cancer. As patients may acquire resistance-mediating mutations within the extracellular EGFR domain, functional dissection of the exact binding sites of EGFR targeting antibodies may help predict treatment responses. We therefore assessed the epitope recognition of panitumumab by screening phage-displayed random cyclic 7mer and linear 12mer peptide libraries on this antibody. Phage screenings revealed two strong, potentially epitope-mimicking consensus motifs targeted by panitumumab. A computational approach was used to map the sequences back to the potential epitope region on domain III of EGFR. The presumed epitope regions (386)WPEXRT(391) and a biochemically similar though discontinuous region P349-F352-D355 on a neighboring loop of domain III could be confirmed as part of the functionally relevant binding site of panitumumab by site-directed mutational analysis. To more accurately differentiate the panitumumab epitope from the previously characterized cetuximab epitope, binding studies were performed on a broad range of additional mutants. Taken together, this analysis revealed two large, partially overlapping functional epitopes consisting of 17 critical amino acid positions. Four of these positions were selectively targeted by cetuximab (I467, S468, Q408, and H409), whereas another four were selectively recognized by panitumumab (W386, E388, R390, and T391). In view of the clinical significance of extracellular domain mutations, our data may help guide treatment decisions in selected patients receiving EGFR-targeted therapies.
KW - Humans
KW - Mutation
KW - Models, Molecular
KW - Protein Conformation
KW - Protein Binding
KW - Peptide Library
KW - Antibodies, Monoclonal/chemistry/immunology/metabolism
KW - Cell Surface Display Techniques
KW - Epitope Mapping
KW - Epitopes/chemistry/genetics/immunology/metabolism
KW - Molecular Mimicry/immunology
KW - Peptides/immunology/metabolism
KW - Receptor, Epidermal Growth Factor/genetics/immunology/metabolism
KW - Humans
KW - Mutation
KW - Models, Molecular
KW - Protein Conformation
KW - Protein Binding
KW - Peptide Library
KW - Antibodies, Monoclonal/chemistry/immunology/metabolism
KW - Cell Surface Display Techniques
KW - Epitope Mapping
KW - Epitopes/chemistry/genetics/immunology/metabolism
KW - Molecular Mimicry/immunology
KW - Peptides/immunology/metabolism
KW - Receptor, Epidermal Growth Factor/genetics/immunology/metabolism
U2 - 10.1593/neo.121242
DO - 10.1593/neo.121242
M3 - SCORING: Journal article
VL - 14
SP - 1023
EP - 1031
JO - NEOPLASIA
JF - NEOPLASIA
SN - 1476-5586
IS - 11
M1 - 11
ER -
