Novel AAV2 capsid expressing Aflibercept shows efficacy and sustainability in rabbit DL-AAA model at picogram level

Abstract

Purpose : The objective of the study is to test the ABI-110 (engineered AAV2 expressing Aflibercept, rAAV2.N54-Aflibercept) in a rabbit DL-AAA model for efficacy and sustainability.

Methods : In-life study was performed by injecting DL-AAA in the left eye (OS) and after 17 days of induction, ABI-110 (low dose (LD) = 2.0E+10 vg/eye; high dose (HD) = 2.0E+11 vg/eye), commercial Eylea® (200 µg/eye) and vehicle were injected into both eyes (OU). FA imaging was performed every 2 weeks. Aflibercept analysis in aqueous humor (AH), vitreous humor (VH), retinal tissues, and other organs was performed using GLP-validated sandwich Aflibercept ELISA.

Results : Injection of DL-AAA induced severe leakage conditions in all the OS eyes. The leakage was reversed in eyes injected with ABI-110 and in Eylea® within 1 week of IVT. Both LD and HD had similar efficacy in reducing the leakage throughout the study duration that lasted for 3 months. Eylea®-injected animals showed a typical plot of leakage reversal till 60-70 days followed by leakage similar to vehicle-injected animals where there was no leakage protection. Aflibercept ELISA in AH showed very high levels of 500 ng/mL and 90 ng/mL at Day 20 and 33 respectively for the Eylea® injected group but swiftly came down to baseline at Day 70. ABI-110 (LD and HD) showed a sustained expression of 20 ng/mL throughout the study. In retinal tissue and retinal pigment epithelium (RPE/CHR) at Day 106, ABI-110 (LD and HD) showed 150 pg/mg tissue. While the Eylea® group showed a high concentration in serum (~300 ng/mL), ABI-110 showed values below detection limits (0.1 ng/mL).

Conclusions : AAV2 capsid was engineered (rAAV2.N54) using directed evolution by introducing mutation at 587 position. This insertion facilitated the deep penetrability of the AAV reaching the RPE layer. ABI-110 showed efficacy similar to the Eylea® group even though the AH concentrations were 25-fold lower in ABI-110 animals. The concentration remained around 20 ng/mL throughout the study showing sustainability, unlike Eylea®. ABI-110 was locally expressed and wasn’t found in serum or other organs. The data shows that Aflibercept at the picogram level is sufficient to show similar efficacy as commercial Eylea® but with greater sustainability.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Retinal Vascular Leakage of Eyes Treated with Eylea, Vehicle and ABI-110