Abstract
Stem cell factor (SCF) and its receptor, cKIT, are novel regulators of pathological neovascularization in the eye, which suggests that inhibition of SCF/cKIT signaling may be a novel pharmacological strategy for treating neovascular age-related macular degeneration (AMD). This study evaluated the therapeutic potential of a newly developed fully human monoclonal antibody targeting cKIT, NN2101, in a murine model of neovascular AMD. In hypoxic human endothelial cells, NN2101 substantially inhibited the SCF-induced increase in angiogenesis and activation of the cKIT signaling pathway. In a murine model of neovascular AMD, intravitreal injection of NN2101 substantially inhibited the SCF/cKIT-mediated choroidal neovascularization (CNV), with efficacy comparable to aflibercept, a vascular endothelial growth factor inhibitor. A combined intravitreal injection of NN2101 and aflibercept resulted in an additive therapeutic effect on CNV. NN2101 neither caused ocular toxicity nor interfered with the early retinal vascular development in mice. Ocular pharmacokinetic analysis in rabbits indicated that NN2101 demonstrated a pharmacokinetic profile suitable for intravitreal injection. These findings provide the first evidence of the potential use of the anti-cKIT blocking antibody, NN2101, as an alternative or additive therapeutic for the treatment of neovascular AMD.
Highlights
We investigated the therapeutic efficacy of NN2101 in a murine model of neovascular age-related macular degeneration (AMD) and determined the ocular toxicity and pharmacokinetics (PK) of NN2101
We investigated the blocked the Stem cell factor (SCF)-induced increase in migration and tube formation of murine endothelialtherapeut effect of NN2101 on pathological in the choroid usingofaNN2101 commonallowed murine model cells
Quantitative analysis roidal tissues of mice exhibited a substantial decrease in th of choroidal neovascularization (CNV) lesions revealed that intravitreal administration of NN2101 significantly reduced phosphorylation of cKIT, glycogen synthase kinase (GSK)-3β, and β-catenin to levels as low as that in the choroid the area of CNV lesions compared with the vehicle (Figure 2B)
Summary
The pathology of neovascular AMD is characterized by choroidal neovascularization (CNV), where new immature blood vessels exhibit growth from the underlying choriocapillary into the subretinal pigment epithelium or subretinal space [2] These immature blood vessels present with leakage of fluids and blood into and under the retina, leading to vision loss or distortion. We previously identified stem cell factor (SCF) and its receptor, cKIT, as novel targets for neovascular eye diseases [12]. The expression of SCF and cKIT is highly upregulated in patients with active PDR compared to that in patients with quiescent PDR or nondiabetic patients [13,14] These findings suggest that anti-SCF/cKIT therapy is a promising therapeutic strategy for treating neovascular eye diseases. We investigated the therapeutic efficacy of NN2101 in a murine model of neovascular AMD and determined the ocular toxicity and pharmacokinetics (PK) of NN2101
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