The Structural Basis for the Function of Two Anti-VEGF Receptor 2 Antibodies

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. ► 1121B and 6.64 both block VEGF binding to KDR, but do so in completely different ways ► CDR H2 in 1121B sterically clashes with a loop in bound VEGF-C (and probably VEGF-A ► 6.64 blocks VEGF binding to AP-tagged KDR, but not to the Fc-tagged equivalent ► The 1121B and VEGF contact surfaces on KDR domain 3 abut, but do not overlap