Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage.

Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision-loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin αβ ligand present in the extracellular matrix. Single-cell transcriptomics reveal MFAP4 expression in cell-types in close proximity to vascular endothelial cells including choroidal vascular mural cells and retinal astrocytes and Müller cells. Binding of the anti-MFAP4 antibody, hAS0326, makes MFAP4 inaccessible for integrin receptor interaction and thereby hAS0326 blocked endothelial cell motility in vitro. Intravitreal hAS0326 inhibited retinal vascular lesion area and neovessel volume in a laser-induced choroidal neovascularization mouse model, vascular permeability in streptozotocin-induced retinopathy and vascular leakage area in a chronic non-human primate model of DL-2-aminoadipic acid-induced retinopathy. One dose of hAS0326 showed duration of efficacy of at least 12 weeks in the latter model. Moreover, hAS0326-treatment significantly enriched gene ontology terms involving reduction of integrin binding. Our data suggest that hAS0326 constitutes a promising treatment of neovascularization and vascular leakage in retinal diseases.