title: The structural basis for the function of two anti-VEGF receptor 2 antibodies.
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.
authors.affiliation: Department of Immunology, ImClone Systems, New York, NY 10014, USA. mfranklin@nysbc.org
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Franklin
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Navarro
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wang
authors.forename: Sheetal
authors.initials: S
authors.lastname: Patel
authors.forename: Pinki
authors.initials: P
authors.lastname: Singh
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kris
authors.initials: K
authors.lastname: Persaud
authors.forename: Amtul
authors.initials: A
authors.lastname: Bari
authors.forename: Heather
authors.initials: H
authors.lastname: Griffith
authors.forename: Leyi
authors.initials: L
authors.lastname: Shen
authors.forename: Paul
authors.initials: P
authors.lastname: Balderes
authors.forename: Paul
authors.initials: P
authors.lastname: Kussie
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity; D001666:Binding Sites, Antibody; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry* / Q000235:genetics; D000096662:Ramucirumab
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040301:Vascular Endothelial Growth Factor Receptor-2; D000096662:Ramucirumab