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Specific ablation of PDGFRβ-overexpressing pericytes with antibody-drug conjugate potently inhibits pathologic ocular neovascularization in mouse models
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Specific ablation of PDGFRβ-overexpressing pericytes with antibody-drug conjugate potently inhibits pathologic ocular neovascularization in mouse models
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Specific ablation of PDGFRβ-overexpressing pericytes with antibody-drug conjugate potently inhibits pathologic ocular neovascularization in mouse models
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Journal Article
Specific ablation of PDGFRβ-overexpressing pericytes with antibody-drug conjugate potently inhibits pathologic ocular neovascularization in mouse models
2021
Overview
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 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.
Methods
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.
Results
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.
Conclusion
Our results suggest that removing PDGFRβ-expressing pericytes by an ADC targeting PDGFRβ could be a potential therapeutic strategy for pathologic ocular neovascularization.
Plain language summary
Many diseases of the eye, such as age-related macular degeneration, involve abnormal blood vessel formation in the eye. One way to treat these diseases is to block the formation of blood vessels, for example by targeting cells called pericytes that surround small blood vessels. Here, we test a pericyte-targeting antibody-drug conjugate – in which a protein that can target a specific molecule on the cell surface is chemically linked to a drug that kills cells – for its ability to block blood vessel formation. We demonstrate that this approach is safe and effective in two mouse models. Our findings suggest that this might be a potentially useful strategy to treat these diseases in patients, for example when existing therapies no longer work.
Lee et al. use an antibody-drug conjugate to treat pathologic ocular neovascularization in mouse models. The antibody-drug conjugate targets PDGFRβ-expressing pericytes, with similar therapeutic effects to an anti-VEGF agent and with limited unwanted toxicity.
