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Tine Van Bergen, Tjing-Tjing Hu, Isabelle Etienne, Geert Reyns, Jean Feyen; The effect of combined PlGF and VEGF inhibition on vascular leakage and inflammation in experimental murine models. Invest. Ophthalmol. Vis. Sci. 2019;60(9):980.
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© ARVO (1962-2015); The Authors (2016-present)
Neutralization of placental growth factor (PlGF) has preclinically shown equal efficacy compared to VEGF inhibition on vascular leakage but differentiates itself by reducing inflammation and fibrosis, with no impact on the neuroretina. In this study, the potential benefit of the combined therapy with PlGF and VEGF was explored in animal models.
The in vivo efficacy of repeated intravitreal injections of the anti-PlGF antibody (5D11D4; 5.4 µg/eye) in combination with the anti-VEGF antibody (B20; 5.4 µg/eye) was tested in the diabetic Akimba mouse model (n=32-37/group). Its effect on vascular leakage (fluorescein angiography; FA) and inflammation (Isolectin B4 staining) was compared to the effect of 5D11D4, B20 and equimolar concentration of VEGF-Trap (4.1 µg/eye) as single therapies or PBS as negative control. The combinatorial effect on vascular leakage (FA) and on collagen deposition (Col1a staining) was also evaluated in the laser-induced mouse model of choroidal neovascularization (CNV; n=6-13/group).
In the mouse Akimba model, administration of B20, VEGF-Trap, 5D11D4 and the combination treatment (5D11D4 + B20) reduced retinal vascular leakage at 4 weeks, with 15% (P>0.05), 21% (P=0.056), 32% (P<0.05) and 40% (P<0.01), respectively, as compared to baseline levels. Five weeks after initiation of treatment with VEGF-Trap, 5D11D4 and the combination treatment, the number of Isolectin B4-positive cells had decreased by 59% (P<0.05), 62% (P<0.05) and by 57% (p=0.069 compared to PBS treated eyes), respectively. No effect on inflammation was seen after B20 treatment alone. In the mouse CNV model, B20 significantly reduced vascular leakage by 32% at day 7 after laser (P<0.01), whereas the combined administration of 5D11D4 and B20 showed a reduction of 57%, as compared to the PBS treated eyes (P<0.01). At 30 days post-laser, 5D11D4 significantly reduced collagen deposition with 44% versus buffer-treated eyes (P<0.05). Single therapies of equimolar dosing of VEGF-Trap and B20 had no effect on collagen 1a deposition, whereas the combination of 5D11D4 and B20 significantly reduced fibrosis by 27% (P<0.05).
These preclinical results indicate that combined PlGF and VEGF inhibition showed an additional reduction in leakage as compared to VEGF inhibition, while maintaining its anti-inflammatory and anti-fibrotic effects.Financial disclosure: Oxurion NV.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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