Targeting Tissue Factor for Immunotherapy of Choroidal Neovascularization by Intravitreal Delivery of Factor VII-Fc Chimeric Antibody

Abstract

Purpose: ICON is a fusion protein composed of factor VII, the natural ligand for tissue factor, conjugated to the Fc domain of a human IgG1 immunoglobulin. It binds to the tissue factor expressed on neovascular endothelia and initiates a cytolytic immune attack that destroys the neovascular tissue. We previously showed that mouse factor VII-Fc chimeric antibody (mICON) dramatically decreases the frequency of choroidal neovascularization in a laser-induced choroidal neovascularization model in mice. Herein, we determined the safety and efficacy of mICON in destroying subretinal choroidal neovascularization in pig eyes. Methods: mICON (150–1200 μg) was administered into the midvitreous cavity of the pig eye either before (on Day 0) or after (on Day 10) induction of choroidal neovascularization with laser photocoagulation. On Day 14, the incidence of choroidal neovascularization was determined using confocal microscopy. We also determined the binding specificity (% binding to choroidal neovascularization/% binding to non-choroidal neovascularization areas) of mICON to tissue factor expressed on endothelial cells of laser-induced choroidal neovascularization. Results: We observed that mICON selectively destroyed choroidal neovascularization in a dose-dependent manner (r = −0.93; EDB_50B = 571.3 μg). Obliteration of the choroidal neovascular complex was more prominent at doses > 300 μg (p < 0.05). No systemic or local complications (including retinal tear/detachment, inflammation, infection, cataract, or glaucoma) were observed. Binding specificities of hICON (2.2 ± 0.2) and mICON (3.4 ± 0.4) were significantly higher than that of anti-von Willebrand antibody (0.1 ± 0.01, p < 0.001). Conclusions: Both hICON and mICON bound to the neovascular endothelia of choroidal neovascularization with greater specificity than anti-von Willebrand antibody. Furthermore, mICON can selectively obliterate already established choroidal neovascularization, which suggests that it may be useful for immunotherapy in patients with exudative (wet) macular degeneration.

KEYWORDS:

• Age-related macular degeneration
• neovascularization
• immunotherapy
• angiogenesis
• intravitreal drug delivery