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Aflibercept Suppression of Angiopoietin-2 in a Rabbit Retinal Vascular Hyperpermeability Model
Claudia Lange1,2, Reimo Tetzner3,4, Tobias Strunz5,6
1Research & Development, Precision Medicine Markers, Bayer AG, Berlin, Germany.
Purpose:
Anti-vascular endothelial growth factor (anti-VEGF) therapies, which attenuate the capacity of VEGF to bind to VEGF receptors, are standard-of-care options for various retinal disorders that are characterized by pathologic retinal angiogenesis and vascular permeability. Multiple receptors and ligands have also been reported as being involved in these pathways, including angiopoietin-1 (ANG1) and angiopoietin-2 (ANG2).
Methods:
Electrochemiluminescence immunoassays were used to detect human VEGF (hVEGF), as well as rabbit ANG2 and basic fibroblast growth factor protein levels in vitreous samples derived from a study evaluating the efficacy of the anti-VEGF agents ranibizumab, aflibercept, and brolucizumab in an hVEGF165-induced rabbit retinal vascular hyperpermeability model.
Results:
hVEGF was completely suppressed in rabbit vitreous after anti-VEGF treatment for 28 days. ANG2 protein in vitreous and ANGPT2 mRNA in retina tissue were similarly suppressed, although the anti-VEGF agents do not directly bind to ANG2. Aflibercept demonstrated the greatest inhibitory effect in ANG2 levels in vitreous, which correlated with strong, durable suppression of intraocular hVEGF levels.
Conclusions:
This study explored the effects of anti-VEGF therapies beyond direct binding of VEGF by evaluating protein levels and the expression of target genes involved in angiogenesis and associated molecular mechanisms in the rabbit retina and choroid.
Translational Relevance:
In vivo data suggest that anti-VEGF agents currently used for the treatment of retinal diseases could provide beneficial effects beyond direct binding of VEGF, including suppression of ANG2 protein and ANGPT2 mRNA.
Insights
Anti-vascular endothelial growth factor (anti-VEGF) therapies suppress angiopoietin-2 (ANG2) protein and ANGPT2 mRNA in retinal disease models. These findings suggest anti-VEGF treatments offer benefits beyond direct VEGF pathway inhibition.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Anti-vascular endothelial growth factor (anti-VEGF) therapies are standard treatments for retinal disorders.
- Pathologic retinal angiogenesis and vascular permeability involve VEGF, angiopoietin-1 (ANG1), and angiopoietin-2 (ANG2) pathways.
Purpose of the Study:
- To investigate the effects of anti-VEGF therapies beyond direct VEGF binding.
- To evaluate protein and gene expression in angiogenesis-related pathways in a rabbit model.
Main Methods:
- Used electrochemiluminescence immunoassays to measure human VEGF (hVEGF), rabbit ANG2, and basic fibroblast growth factor.
- Analyzed vitreous and retinal tissue samples from a rabbit model of hVEGF165-induced retinal vascular hyperpermeability.
Main Results:
- Anti-VEGF treatment suppressed hVEGF, ANG2 protein, and ANGPT2 mRNA in rabbit eyes.
- Aflibercept showed the most significant inhibition of ANG2 levels, correlating with sustained hVEGF suppression.
- Anti-VEGF agents do not directly bind ANG2, indicating an indirect mechanism of suppression.
Conclusions:
- Anti-VEGF therapies may exert beneficial effects by suppressing ANG2 protein and ANGPT2 mRNA.
- These findings suggest broader therapeutic mechanisms for anti-VEGF agents in retinal diseases.
