Intravitreal administration, but not systemic administration, of VEGF Mini-Trap effectively inhibits neovascularization in the Oxygen Induced Retinopathy (OIR) in mice

Abstract

Purpose : Vascular Endothelial Growth Factor (VEGF) plays an essential role in normal and pathological angiogenesis. Aflibercept is a potent VEGF inhibitor that binds all isoforms of VEGF-A as well as the VEGFR1 ligands placental growth factor (PlGF) and VEGF-B. When administered systemically (IP) or intravitreally (IVT), VEGF Trap effectively blocks pathological retinal neovascularization in OIR model (IOVS 2006; 47:E-Abstract 1750; IOVS 2011:E-Abstract 3210). In this study, we evaluated the effects of aflibercept (full length) in comparison to VEGF Mini-Trap (REGN7483, Fc cleaved aflibercept) in the murine OIR model.

Methods : C57Bl6 mouse pups were placed in a hyperoxic environment (75% O₂) at postnatal day (P)6 and returned to room air at P11. Study 1 (IVT Screen Study): OIR pups were injected IVT with human Fc 0.25µg, aflibercept 0.125ug, or REGN7483 0.125µg, respectively, at P13 and collected at P16. Study 2 (IVT Dose Response Study): OIR mice were injected IVT with Fc 0.25µg, REGN7483 at 0.025µg, 0.25µg, and 2.5µg, or aflibercept at 0.05µg, 0.5µg, and 5µg at P13 and collected at P16. Study 3 (IP Study): OIR mice were injected IP with Fc 5mg/kg, aflibercept 10mg/kg, or REGN7483 at 5mg/kg, 15mg/kg, and 50mg/kg, respectively, at P12 and collected at P16.

Results : Study 1: Although at equimolar doses IVT Fc, aflibercept, and REGN7483 showed similar avascular areas, aflibercept and REGN7483 notably reduced neovascular tufts compared to Fc. Study 2: IVT aflibercept and REGN7483 reduced tufts in a dose-dependent manner, compared to Fc. There were no differences in abnormal area between aflibercept and REGN7483 at matched molar doses. Study 3: IP aflibercept resulted in a significant tuft reduction, compared to Fc and all REGN7483 groups.

Conclusions : These studies in mice show that VEGF Mini-Trap administered IVT and not systemically demonstrated anti-angiogenic activity. These studies validate that VEGF Mini-Trap dose-dependently inhibits pathological neovascularization. These studies also document the equipotency of intravitreal VEGF Mini-Trap with intravitreal full-length aflibercept. The lack of systemic efficacy of Mini-Trap is likely due to more rapid clearance systemically, although this study did not directly measure PK.

This is a 2021 ARVO Annual Meeting abstract.