7ZMK

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

7ZMK の概要

• エントリーDOI: 10.2210/pdb7zmk/pdb
• 分子名称: Microfibril-associated glycoprotein 4, heavy chain of antibody AS0326, Light chain of AS0326, ... (5 entities in total)
• 機能のキーワード: antibody, mfap4, extracellular matrix, cell adhesion
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 24
• 化学式量合計: 611836.45

構造登録者

Laursen, N.S.,Andersen, G.R. (登録日: 2022-04-19, 公開日: 2023-03-01, 最終更新日: 2025-02-05)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.4 Å)