A Fully Human Monoclonal Antibody Targeting c-KIT is a Potent Inhibitor of Choroidal Neovascularization in Murine Model of Neovascular Age-Related Macular Degeneration

초록

Purpose : In our previous study, stem cell factor (SCF) and its receptor, cKIT, are identified as novel regulators of angiogenesis at hypoxia and pathological neovascularization in the eye, which suggests that suppression of SCF/cKIT signaling would be a new pharmacological strategy for the treatment of ocular vascular diseases such as neovascular age-related macular degeneration (nAMD). In this regard, the present study aims to determine the efficacy and safety of newly developed fully human monoclonal IgG targeting cKIT (NN2101) in the murine model of nAMD. Methods : Inhibitory effect of NN2101 on SCF-induced angiogenesis was evaluated by western blotting and in vitro angiogenesis assays. Efficacy of intravitreal injection of NN2101 alone and its combination with aflibercept was determined using mice with laser injury-induced choroidal neovascularization (CNV). One week later, choroidal tissues were harvested for further analysis. Ocular toxicity and pharmacokinetics of intravitreal injection of NN2101 were assessed in mice and rabbits, respectively. All data were analyzed for normality, followed by an unpaired Student’s t-test, one-way ANOVA with Bonferroni’s test, or Kruskal-Wallis test. Results : In hypoxic human vascular endothelial cells, NN2101 completely blocked the SCF-induced activation of cKIT/β-catenin signaling pathways and increase in cell migration, tube formation, and proliferation. In mice with laser-induced CNV, an intravitreal injection of NN2101 (1.0 µg) significantly alleviated CNV formation with a comparable efficacy of aflibercept (2.5 µg) (Kruskal-Wallis test, *p < 0.01, n > 6 mice). Combined intravitreal injection of suboptimal doses of NN2101 and aflibercept substantially enhanced anti-angiogenic efficacy (Kruskal-Wallis test, *p < 0.05, n > 7 mice). In addition, NN2101 neither caused ocular toxicity nor interfered early retinal vascular development in mice. Ocular Pharmacokinetic analysis of the rabbits after intravitreal injection administration of NN2101 showed that NN2101 rapidly distributed and remained in retinal and choroidal tissues even after 30 days or more. Conclusions : NN2101, a fully human monoclonal antibody targeting cKIT, may be a novel promising therapeutic and can enhance the potency of existing anti-vascular endothelial growth factor agents for the treatment of nAMD. This is a 2021 ARVO Annual Meeting abstract.