Antibody blockade of Jagged1 attenuates choroidal neovascularization

Torleif Tollefsrud Gjølberg, Jonas Aakre Wik, Hanna Johannessen, Stig Krüger, Nicola Bassi, Panagiotis F. Christopoulos, Malin Bern, Stian Foss, Goran Petrovski, Morten C. Moe, Guttorm Haraldsen, Johanna Hol Fosse, Bjørn Steen Skålhegg, Jan Terje Andersen () and Eirik Sundlisæter ()
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Torleif Tollefsrud Gjølberg: Oslo University Hospital Rikshospitalet
Jonas Aakre Wik: Oslo University Hospital Rikshospitalet
Hanna Johannessen: Oslo University Hospital Rikshospitalet
Stig Krüger: Oslo University Hospital Rikshospitalet
Nicola Bassi: Oslo University Hospital Rikshospitalet
Panagiotis F. Christopoulos: Oslo University Hospital Rikshospitalet
Malin Bern: Oslo University Hospital Rikshospitalet
Stian Foss: Oslo University Hospital Rikshospitalet
Goran Petrovski: Oslo University Hospital and University of Oslo
Morten C. Moe: Oslo University Hospital and University of Oslo
Guttorm Haraldsen: Oslo University Hospital Rikshospitalet
Johanna Hol Fosse: Oslo University Hospital Rikshospitalet
Bjørn Steen Skålhegg: University of Oslo
Jan Terje Andersen: Oslo University Hospital Rikshospitalet
Eirik Sundlisæter: Oslo University Hospital Rikshospitalet

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38563-w

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