Functional Characterization of Abicipar-Pegol, an Anti-VEGF DARPin Therapeutic That Potently Inhibits Angiogenesis and Vascular Permeability.

PURPOSE: DARPin molecules are a novel class of small proteins that contain engineered ankyrin repeat domain(s) and bind to target proteins with high specificity and affinity. Abicipar-pegol (abicipar), a DARPin molecule targeting vascular endothelial growth factor-A (VEGF-A), is currently under evaluation in patients with age-related macular degeneration. The pharmacodynamic properties of abicipar were characterized using in vivo and in vitro assays.

METHODS: The binding affinity of abicipar was assessed using a kinetic exclusion assay (KinExA). In vitro assays evaluated abicipar effects on VEGF-A165-induced calcium mobilization and tube formation in human umbilical vein endothelial cells. Abicipar was tested in vivo in a mouse model of corneal neovascularization and a rabbit model of chronic retinal neovascularization. The efficacies of abicipar and ranibizumab were compared in a rabbit model of VEGF-A165-induced retinal vasculopathy.

RESULTS: Abicipar has a high affinity for the soluble isoforms of VEGF-A; binding affinities for human VEGF-A165 are approximately 100-fold greater than those of ranibizumab and bevacizumab and are similar for rat VEGF-A164 but approximately 20-fold lower for rabbit VEGF-A165. Abicipar was effective in cell-based and in vivo models of angiogenesis and vascular leak, blocking neovascularization in a mouse model of corneal neovascularization and vascular permeability in a rabbit model of chronic neovascularization. In a rabbit model of VEGF-A165-induced vasculopathy, the duration of effect of abicipar was longer than ranibizumab when the two compounds were administered at molar-equivalent doses.

CONCLUSIONS: These data support the testing of abicipar as a treatment for retinal diseases characterized by neovascularization and vascular leak.