7ZMK

Structure of human MFAP4 in complex with the Fab fragment of the AS0326 monoclonal antibody

Summary for 7ZMK

• Entry DOI: 10.2210/pdb7zmk/pdb
• Descriptor: Microfibril-associated glycoprotein 4, heavy chain of antibody AS0326, Light chain of AS0326, ... (5 entities in total)
• Functional Keywords: antibody, mfap4, extracellular matrix, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 24
• Total formula weight: 611836.45

Authors

Laursen, N.S.,Andersen, G.R. (deposition date: 2022-04-19, release date: 2023-03-01, Last modification date: 2025-02-05)

Primary citation

Schlosser, A.,Pilecki, B.,Allen, C.,Benest, A.V.,Lynch, A.P.,Hua, J.,Ved, N.,Blackley, Z.,Andersen, T.L.,Hennig, D.,Graversen, J.H.,Moller, S.,Skallerup, S.,Ormhoj, M.,Lange, C.,Agostini, H.T.,Grauslund, J.,Heegaard, S.,Dacheva, I.,Koss, M.,Hu, W.,Iglesias, B.,Lawrence, M.S.,Beck, H.C.,Steffensen, L.B.,Laursen, N.S.,Andersen, G.R.,Holmskov, U.,Bates, D.O.,Sorensen, G.L.
Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage.
Mol.Ther., 2025

PubMed Abstract: 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, 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.

PubMed: 39863929
DOI: 10.1016/j.ymthe.2025.01.038

Experimental method

X-RAY DIFFRACTION (3.4 Å)