Antibody blockade of Jagged1 attenuates choroidal neovascularization

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...

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Published in:	Nature communications 2023-05, Vol.14 (1), p.3109-3109, Article 3109
Main Authors:	Gjølberg, Torleif Tollefsrud, Wik, Jonas Aakre, Johannessen, Hanna, Krüger, Stig, Bassi, Nicola, Christopoulos, Panagiotis F, Bern, Malin, Foss, Stian, Petrovski, Goran, Moe, Morten C, Haraldsen, Guttorm, Fosse, Johanna Hol, Skålhegg, Bjørn Steen, Andersen, Jan Terje, Sundlisæter, Eirik
Format:	Article
Language:	eng ; nor
Subjects:	Age Age related diseases Angiogenesis Inhibitors - therapeutic use Animals Antibodies Antibodies, Blocking - therapeutic use Blocking Choroidal Neovascularization - pathology Disease Models, Animal Edema Endothelial cells Endothelial Cells - metabolism Eye diseases Growth factors Health services Humans Inflammation Jagged1 protein Lesions Macular degeneration Mice Monoclonal antibodies Phagocytes Signal Transduction - physiology Vascular endothelial growth factor Vascular Endothelial Growth Factor A - metabolism Vascularization
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Summary:	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.
ISSN:	2041-1723 2041-1723