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Abstract
Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with neovascular age-related macular degeneration (nAMD). However, poor response and resistance to anti-VEGF treatment occurs. We report that targeting the Notch ligand Jagged1 by a monoclonal antibody reduces neovascular lesion size, number of activated phagocytes and inflammatory markers and vascular leakage in an experimental CNV mouse model. Additionally, we demonstrate that Jagged1 is expressed in mouse and human eyes, and that Jagged1 expression is independent of VEGF signaling in human endothelial cells. When anti-Jagged1 was combined with anti-VEGF in mice, the decrease in lesion size exceeded that of either antibody alone. The therapeutic effect was solely dependent on blocking, as engineering antibodies to abolish effector functions did not impair the therapeutic effect. Targeting of Jagged1 alone or in combination with anti-VEGF may thus be an attractive strategy to attenuate CNV-bearing diseases.
Current treatment for neovascular age-related macular degeneration (nAMD) does not help all patients. Here, the authors show that using antibodies to block Jagged1 reduces disease burden in a model of nAMD, which could enable new treatment options.
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1 Oslo University Hospital Rikshospitalet, Department of Immunology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo and Oslo University Hospital, Institute of Clinical Medicine and Department of Pharmacology, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University Hospital and University of Oslo, Center of Eye Research, Department of Ophthalmology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485)
2 Oslo University Hospital Rikshospitalet, Department of Pathology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Department of Nutrition, Division of Molecular Nutrition, Institute of Basic Medical Sciences, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921)
3 Oslo University Hospital Rikshospitalet, Department of Pathology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); Oslo University Hospital Rikshospitalet, Department of Pediatric Surgery, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485)
4 Oslo University Hospital Rikshospitalet, Department of Pathology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485)
5 Oslo University Hospital Rikshospitalet, Department of Immunology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo and Oslo University Hospital, Institute of Clinical Medicine and Department of Pharmacology, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921)
6 Oslo University Hospital and University of Oslo, Center of Eye Research, Department of Ophthalmology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485)
7 University of Oslo, Department of Nutrition, Division of Molecular Nutrition, Institute of Basic Medical Sciences, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921)