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Monoclonal antibodies that block Roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells

细胞生物学 生物 免疫学 癌症研究 血管生成 新生血管
作者
Luiz Henrique Geraldo,Yunling Xu,G Mouthon,Jessica Furtado,Felipe Saceanu Leser,Levi L. Blazer,Jarrett Adams,Sophia Zhang,L Zheng,Eric Song,Mark E. Robinson,Jean‐Léon Thomas,Sachdev S. Sidhu,Anne Eichmann
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science]
卷期号:16 (774) 被引量:1
标识
DOI:10.1126/scitranslmed.adn8388
摘要

Roundabout (ROBO) 1 and 2 are transmembrane receptors that bind secreted SLIT ligands through their extracellular domains (ECDs) and signal through their cytoplasmic domains to modulate the cytoskeleton and regulate cell migration, adhesion, and proliferation. SLIT-ROBO signaling regulates pathological ocular neovascularization, which is a major cause of vision loss worldwide, but pharmacological tools to prevent SLIT-ROBO signaling are lacking. Here, we developed human monoclonal antibodies (mAbs) against the ROBO1 and ROBO2 ECDs. One antibody that inhibited in vitro SLIT2 signaling through ROBO1 and ROBO2 (anti-ROBO1/2) also reduced ocular neovascularization in oxygen-induced retinopathy (OIR) and laser-induced corneal neovascularization (CNV) mouse models in vivo. Single-cell RNA sequencing of OIR retinas revealed that antibody treatment affected several cell types relevant to physiological and pathological angiogenesis, including endothelial cells, pericytes, and a heterogeneous population of myeloid cells. mAb treatment improved blood-retina barrier integrity and prevented pathological pericyte activation in OIR. SLIT-ROBO signaling inhibition prevented pathological activation of myeloid cells and increased neuroprotective myeloid populations normally seen in the developing retina. Microglia/infiltrating macrophage–specific ablation of Robo1 and Robo2 or knockout of the downstream effector phosphatidylinositol 3-kinase ( Pik3cg ) encoding PI3Kγ in both OIR and CNV models phenocopied anti-ROBO1/2 treatment, further demonstrating the key role of myeloid cells as drivers of ocular neovascular diseases. ROBO1/2 blocking antibodies may thus provide a promising strategy to combat inflammation in blinding eye diseases.
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