Abstract
Purpose :
To validate and standardize the use of intravitreally (IVT) and systemically-administered aflibercept as reference compound in preclinical rodent models for angiogenesis.
Methods :
Three rodent models for angiogenesis were used: 1. oxygen-induced retinopathy (OIR); 2. choroidal neovascularization (CNV); and 3. streptozotocin (STZ)-induced diabetic retinopathy. Aflibercept (Eylea®) was delivered IVT (4–80 μg) or intraperitoneally (i.p.; 5, 15, 25 mg/kg). Spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA) and vitreofluorophotometry (VFP) were used to longitudinally quantify disease pathology in vivo. Histological analysis of retinal and choroidal flatmounts served as secondary validation of in vivo findings.
Results :
In the mouse OIR model, IVT injection of aflibercept significantly increased retinal avascular area compared to non-treated control (17% vs. 24% of retinal area, n=12, P<0.05) or PBS-injected eyes (11% vs. 24% of retinal arean=17, P<0.001). At the same time, aflibercept significantly decreased neovascularization (n=18, P<0.001). Intriguingly, i.p. injection of aflibercept (80 μg) did not affect vascular obliteration compared to PBS-injected mice (n = 12, P=0.99), however, significantly decreased neovascularization (6% vs. 3% of retinal area, P<0.05). In the rat OIR model, aflibercept increased avascular area by 213% (P<0.001), while reducing neovascularization by 82% (P<0.05). In the mouse CNV model, aflibercept dose-dependently reduced retinal vascular leakage and presence of CNV 5 days after induction of CNV when administered IVT at 40 μg and 80 μg and i.p. at doses of 15 and 25 mg/kg. At later time-points, there was no statistically significant difference in the presence of CNV. In the rat STZ model, aflibercept partially prevented retinal vascular leak when administered IVT, as determined by VFP.
Conclusions :
Aflibercept is efficacious in attenuating disease-relevant functional phenotypes in preclinical models for ocular angiogenic conditions, including the mouse and rat OIR model, the mouse and rat CNV model, and the rat STZ model. Our data confirm and expand on previous reports of the preclinical efficacy of aflibercept, and provide important benchmark datasets for the standardization of the use of aflibercept as reference compound in preclinical drug discovery studies in models of angiogenesis.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.