Doctor of Philosophy, Seoul National University (2020)
Bachelor of Science, University of Auckland (2015)
Peter Kim, Postdoctoral Faculty Sponsor
Specific ablation of PDGFRbeta-overexpressing pericytes with antibody-drug conjugate potently inhibits pathologic ocular neovascularization in mouse models.
2021; 1: 58
Background: Crosstalk between pericytes and endothelial cells is critical for ocular neovascularization. Endothelial cells secrete platelet-derived growth factor (PDGF)-BB and recruit PDGF receptor beta (PDGFRbeta)-overexpressing pericytes, which in turn cover and stabilize neovessels, independent of vascular endothelial growth factor (VEGF). Therapeutic agents inhibiting PDGF-BB/PDGFRbeta 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.Methods: Immunoblotting, flow cytometry, cell viability test, and confocal microscopy were conducted to assess the internalization and cytotoxic effect of ADC targeting mPDGFRbeta 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 mPDGFRbeta in the mouse models of pathologic ocular neovascularization.Results: ADC targeting mPDGFRbeta is effectively internalized into mouse brain vascular pericytes and showed significant cytotoxicity compared with the control ADC. We also show that specific ablation of PDGFRbeta-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.Conclusion: Our results suggest that removing PDGFRbeta-expressing pericytes by an ADC targeting PDGFRbeta could be a potential therapeutic strategy for pathologic ocular neovascularization.
View details for DOI 10.1038/s43856-021-00059-3
View details for PubMedID 35602228