BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of RetinopathiesS

Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. Despite an established standard of care for advanced forms of DR, some patients continue to lose vision af -ter treatment. This may be due to the development of diabetic macular ischemia (DMI), which has no approved treatment. Neuropilin-1 (Nrp-1) isa coreceptor with two ligand-binding do-mains, with semaphorin-3A (Sema3A) binding to the A-domain and vascular endothelial growth factor-A (VEGF-A) binding to the B-domain. Sema3A directs a subset of neuronal growth cones as well as blood vessel growth by repulsion; when bound to Nrp-1, VEGF-A mediates vascular permeability and angio-genesis. Modulating Nrp-1 could therefore address multiple complications arising from DR, such as diabetic macular edema (DME) and DMI. BI-Y is a monoclonal antibody that binds to the Nrp-1 A-domain, antagonizing the effects of the ligand Sema3A and inhibiting VEGF-A-induced vascular permeability. This se-ries of in vitro and in vivo studies examined the binding kinet-ics of BI-Y to Nrp-1 with and without VEGF-A165, the effect of BI-Y on Sema3A-induced cytoskeletal collapse, the effect of BI-Y on VEGF-A165-induced angiogenesis, neovascularization, cell integrity loss and permeability, and retinal revascularization. The data show that BI-Y binds to Nrp-1 and inhibits Sema3A-in-duced cytoskeletal collapse in vitro, may enhance revasculari-zation of ischemic areas in an oxygen-induced retinopathy mouse model, and prevents VEGF-A-induced retinal hyper-permeability in rats. However, BI-Y does not interfere with VEGF-A-dependent choroidal neovascularization. These re-sults support further investigation of BI-Y as a potential treat-ment for DMI and DME. SIGNIFICANCE STATEMENT Diabetic macular ischemia (DMI) is a complication of diabetic retinopathy (DR) with no approved pharmacological treatment. Diabetic macular edema (DME) commonly co-occurs with DMI in patients with DR. This series of preclinical studies in mouse and rat models shows that neuropilin-1 antagonist BI-Y may enhance the revascularization of ischemic areas and prevents vascular endothelial growth factor-A (VEGF-A)-induced retinal hyperpermeability without affecting VEGF-A-dependent cho-roidal neovascularization; thus, BI-Y may be of interest as a po-tential treatment for patients with DR.