Quantification of aflibercept and ranibizumab efficacy in DL-2-aminoadipic acid (DLAAA)-induced retinal neovascularization and vascular leakage in nonhuman primates

Abstract

Purpose : To define the optimal strategy for grading and quantifying the retinal neovascularization and leakage induced by intravitreal (IVT) injection of DLAAA in the green monkey and to further validate the model by evaluating the comparative magnitude of response to IVT aflibercept and ranibizumab treatments.

Methods : DLAAA was administered intravitreally at one dose of 5 mg in adult St. Kitts green monkeys (Chlorocebus sabaeus). Weekly ophthalmic examinations including slit lamp biomicroscopy, color fundus photography, fluorescein angiography and optical coherence tomography were conducted up to 18 weeks. Aflibercept, ranibizumab or normal saline were injected intravitreally at 8 weeks post-DLAAA following randomization of eyes to treatment on the bases of week 8 leakage. The area and fluorescence intensity of retinal vascular leakage were quantified from the 1 and 3 minute angiograms by Amira software (Materials & Structural Analysis, Hillsboro, OR).

Results : Both aflibercept and ranibizumab treatments attenuated the area and fluorescence intensity of retinal vascular leakage, starting from 1 week, peaking around 4 weeks, with gradual reoccurrence of leakage to a level less than the pre-treatment condition at 10 weeks post-administration. Treatment with aflibercept resulted in a 75% reduction in average leakage area in 3 minute angiograms while a 50% reduction was observed in response to ranibizumab. The changes in area and intensity were quite similar between 1 and 3 minute angiograms, however, a complete inhibition of leakage was only observed at the 1 minute angiogram interval in eyes treated with aflibercept.

Conclusions : Measurement of the area and fluorescence intensity of DLAAA-induced neovascularization and leakage using Amira software provides an additional reproducible method for quantitative analysis of retinal vascular leakage. Both aflibercept and ranibizumab treatments significantly reduced retinal vascular leakage, with aflibercept exhibiting a more pronounced effect. Reference to the established behaviour of these control articles in the DLAAA test system and application of these quantitative methods will allow more robust screening of candidate anti-angiogenic compounds.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.