Specific ablation of PDGFRβ-overexpressing pericytes with antibody-drug conjugate potently inhibits pathologic ocular neovascularization in mouse models

• Published in: Communications medicine Vol. 1; no. 1; pp. 58 - 12
• Main Authors: Lee, Seok Jae, Kim, Soohyun, Jo, Dong Hyun, Cho, Chang Sik, Kim, Su Ree, Kang, Dongmin, Chae, Jisu, Yoo, Duck Kyun, Ha, Suji, Chung, Junho, Kim, Jeong Hun
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 08.12.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Breast cancer; Cancer therapies; Cloning; Cytotoxicity; Diabetic retinopathy; Flow cytometry; Lasers; Leukemia; Lymphoma; Monoclonal antibodies; Proteins; Smooth muscle; Vascular endothelial growth factor; United States > US; Target validation; Drug delivery
• ISSN: 2730-664X; 2730-664X
• DOI: 10.1038/s43856-021-00059-3

Crosstalk between pericytes and endothelial cells is critical for ocular neovascularization. Endothelial cells secrete platelet-derived growth factor (PDGF)-BB and recruit PDGF receptor β (PDGFRβ)-overexpressing pericytes, which in turn cover and stabilize neovessels, independent of vascular endothelial growth factor (VEGF). Therapeutic agents inhibiting PDGF-BB/PDGFRβ signaling were tested in clinical trials but failed to provide additional benefits over anti-VEGF agents. We tested whether an antibody-drug conjugate (ADC) - an engineered monoclonal antibody linked to a cytotoxic agent - could selectively ablate pericytes and suppress retinal and choroidal neovascularization. Immunoblotting, flow cytometry, cell viability test, and confocal microscopy were conducted to assess the internalization and cytotoxic effect of ADC targeting mPDGFRβ in an in vitro setting. Immunofluorescence staining of whole-mount retinas and retinal pigment epithelium-choroid-scleral complexes, electroretinography, and OptoMotry test were used to evaluate the effect and safety of ADC targeting mPDGFRβ in the mouse models of pathologic ocular neovascularization. ADC targeting mPDGFRβ is effectively internalized into mouse brain vascular pericytes and showed significant cytotoxicity compared with the control ADC. We also show that specific ablation of PDGFRβ-overexpressing pericytes using an ADC potently inhibits pathologic ocular neovascularization in mouse models of oxygen-induced retinopathy and laser-induced choroidal neovascularization, while not provoking generalized retinal toxicity. Our results suggest that removing PDGFRβ-expressing pericytes by an ADC targeting PDGFRβ could be a potential therapeutic strategy for pathologic ocular neovascularization.