Nature Communications · 15 authors, 6 centres
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In a laser-induced mouse model of choroidal neovascularization, a monoclonal antibody targeting the Notch ligand Jagged1 reduced neovascular lesion size, with an additive effect when combined with anti-VEGF. The therapeutic effect was solely dependent on blocking and was associated with DLL4 upregulation and reduced VEGFR2 expression in endothelial cells.
This preclinical study used a laser-induced mouse CNV model and in vitro HUVEC experiments to evaluate monoclonal antibody blockade of Jagged1 as a therapeutic strategy for neovascular age-related macular degeneration. Anti-Jagged1 treatment alone reduced neovascular lesion size, and combined treatment with anti-VEGF produced an additive effect exceeding either antibody alone. Jagged1 blockade also reduced the number of activated phagocytes, inflammatory markers, and vascular leakage. Mechanistically, Jagged1 blockade led to upregulation of DLL4 in endothelial cells, and DLL4 stimulation reduced VEGFR2 expression in vitro, suggesting DLL4-mediated desensitization to VEGF. The therapeutic effect was solely dependent on blocking, as effector-function-null variants were equally effective. Jagged1 was confirmed to be expressed in mouse and human eyes, and its expression was independent of VEGF signaling in human endothelial cells.
