Brivanib, a multitargeted small‐molecule tyrosine kinase inhibitor, suppresses laser‐induced CNV in a mouse model of neovascular AMD

Abstract

In age-related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially causing serious complications, including vision loss. Vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1) contribute to the pathogenesis of CNV. Brivanib is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of FGFRs and VEGFRs, especially VEGFR2 and FGFR1.In this study, brivanib inhibited zebrafish embryonic angiogenesis without impairing neurodevelopment. In a mouse CNV model, brivanib intravitreal injection blocked phosphorylation of FGFR1 and VEGFR2 and reduced CNV leakage, area, and formation without causing intraocular toxicity. Moreover, brivanib oral gavage reduced CNV leakage and area. Accordingly, brivanib remained at high concentrations (above 14,000 ng/ml) in retinal/choroidal/scleral tissues following intravitreal injection. Similarly, brivanib remained at high concentrations (over 10,000 ng/ml) in retinal/choroidal/scleral tissues following oral gavage. Finally, in vitro cell experiments demonstrated that brivanib inhibited the proliferation, migration and tube formation of microvascular endothelial cells. In conclusion, our study suggested that brivanib treatment could be a novel therapeutic strategy for nAMD. K E Y W O R D Sage-related macular degeneration, choroidal neovascularization, fibroblast growth factor receptor 1, receptor tyrosine kinase inhibitor, vascular endothelial growth factor receptor 2 *Lele Li, Manhui Zhu, Aimin Sang, and Dongmei Ding contributed equally to this work.

Experimental Models in Neovascular Age Related Macular Degeneration

“…Similarly, Li et al [ 56 ] showed the same effects in embryonic zebrafish angiogenesis using brivanib, an inhibitor of FGFR and VEGFR. They also used embryos expressing mCherry under the control of the VEGFR2 promotor (endothelial cells expressing mCherry).…”

Establishing a mouse model of choroidal neovascularization to study the therapeutic effect of levotinib and its mechanism

“…These results suggest that levotinib can inhibit the high expression of VEGF in CNV. The investigation by Li et al ( Li et al, 2020 ) showed that tyrosine kinase inhibitors may inhibit angiogenesis of endometrial tissue in the peritoneum by inhibiting the expression of VEGF-A and HIF-1a ( Li et al, 2020 ). It is almost consistent with the results of this study.…”

Cabozantinib, a Multityrosine Kinase Inhibitor of MET and VEGF Receptors Which Suppresses Mouse Laser-Induced Choroidal Neovascularization

“…e study was performed according to the local institutional laws and the Chinese law for the Protection of Animals. We followed the methods of Li et al [16]. e following transgenic zebrafish types were used: Tg (Flk:mcherry: Hb9:EGFP), which expresses mCherry (red fluorescence) under the control of Flk (also termed vascular endothelial growth factor receptor 2, a vascular endothelial cell marker) and EGFP (green fluorescence) under the control of Hb9 (also termed motor neuron and pancreas homeobox 1, a differentiated motor neuron marker), and Tg (Flk:EGFP), which expresses EGFP (green fluorescence) under the control of the regulatory sequences of Flk.…”

“…VEGFR2 and alleviates the leakage, lesion area, and formation of CNV via intravitreal injection or oral gavage [16].…”