Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab

TLDR

Pharmacological inhibition of VEGF‑A effectively blocks angiogenesis and vascular leak in cancers and eye diseases, yet the binding kinetics of VEGF inhibitors remain poorly characterized. The study evaluated the binding kinetics of ranibizumab, bevacizumab, and VEGF Trap—a soluble decoy receptor with higher affinity than conventional VEGF receptors. VEGF Trap binds all VEGF‑A isoforms with sub‑picomolar affinity, associates orders of magnitude faster, and potently inhibits VEGFR1/2 signaling, calcium mobilization, and endothelial migration, while also binding VEGF‑B and PlGF—features that distinguish it from ranibizumab and bevacizumab.

Abstract

Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF.