Abstract
The anti-VEGF receptor 2 antibody IMC-1121B is a promising antiangiogenic drug being tested for treatment of breast and gastric cancer. We have determined the structure of the 1121B Fab fragment in complex with domain 3 of VEGFR2, as well as the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain 3. The two Fab fragments bind at opposite ends of VEGFR2 domain 3; 1121B directly blocks VEGF binding, whereas 6.64 may prevent receptor dimerization by perturbing the domain 3:domain 4 interface. Mutagenesis reveals that residues essential for VEGF, 1121B, and 6.64 binding are nonoverlapping among the three contact patches.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Angiogenesis Inhibitors / chemistry*
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Antibodies, Monoclonal / chemistry*
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Antibodies, Monoclonal, Humanized
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Antibody Specificity
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Binding Sites, Antibody
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Crystallography, X-Ray
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Enzyme-Linked Immunosorbent Assay
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Models, Molecular
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Protein Binding
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Protein Structure, Quaternary
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Protein Structure, Tertiary
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Ramucirumab
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Vascular Endothelial Growth Factor Receptor-2 / chemistry*
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Vascular Endothelial Growth Factor Receptor-2 / genetics
Substances
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Angiogenesis Inhibitors
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Vascular Endothelial Growth Factor Receptor-2
Associated data
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PDB/3S34
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PDB/3S35
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PDB/3S36
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PDB/3S37