The structural basis for the function of two anti-VEGF receptor 2 antibodies

Structure. 2011 Aug 10;19(8):1097-107. doi: 10.1016/j.str.2011.01.019.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Angiogenesis Inhibitors / chemistry*
  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal, Humanized
  • Antibody Specificity
  • Binding Sites, Antibody
  • Crystallography, X-Ray
  • Enzyme-Linked Immunosorbent Assay
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Ramucirumab
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry*
  • Vascular Endothelial Growth Factor Receptor-2 / genetics

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Vascular Endothelial Growth Factor Receptor-2

Associated data

  • PDB/3S34
  • PDB/3S35
  • PDB/3S36
  • PDB/3S37