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.

A murine–human chimeric IgG antibody against vascular endothelial growth factor receptor 2 inhibits angiogenesis in vitro

“…In addition, Ramucirumab (IMC-1121B, ImClone Systems Corporation, NJ, USA) is a fully human IgG1 mAb that binds to the extracellular domain of VEGFR2, thereby blocking VEGF-VEGFR2 interactions. Phase I and II studies of Ramucirumab have been completed, and Phase III clinical trials are underway (Spratlin et al 2010;Franklin et al 2011). Taken together, these studies demonstrate that the strategy using VEGFR2-targeting mAbs is a promising therapeutic approach for tumor suppression.…”

Ramucirumab – egy új gyógyszer az onkológiában

“…A DC101 gátolta a tumornövekedést egérxenograft-modellben [11]. Mi több, egérmodellben tumorreszekciót követően a DC101 gá-tolta a metasztázisképződést [12]. Mivel a VEGFR-2-ellenes DC101 igazolta a terápiás várakozásokat [13][14][15], így került kifejlesztésre a teljesen humanizált ramucirumab, mivel a humán IgG-1 jóval kevésbé immunogén, mint a nem teljesen humanizált monoklonális antitestek, így a klinikai vizsgálatokban jobban tolerálhatók [16].…”

Ramucirumab for advanced gastric cancer or gastro-oesophageal junction adenocarcinoma

“…A subsequent in vitro selection process, using an additional specific phage display library, selected a high affinity variant for further development [Lu et al 2003]. This variant, clone 1121B, ramucirumab, binds to domain 3, close to the N terminus, and inhibits VEGF-induced signalling by altering the conformation of the receptor, preventing VEGF binding [Franklin et al 2011]. By specifically binding VEGF2, ramucirumab prevents all known VEGFs binding to VEGF2 and therefore could lead to more complete inhibition of angiogenesis than agents directly binding a single VEGF.…”