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Richard H Foxton, Sabine Uhles, Sabine Gruener, Franco Revelant, Nadine Colé, Mirjana Lazendic, Mathieu Brecheisen, Christoph Ullmer; Evaluation of the effects of VEGF/ANG-2 neutralization on vascular, neuronal and inflammatory pathologies in a spontaneous choroidal neovascularization (CNV) mouse model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):237.
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Wet age-related macular degeneration (AMD) and diabetic macula edema (DME) are characterized by vascular hyperpermeability, inflammation, and neuronal loss. We investigated an anti-VEGF/ANG-2 bispecific antibody (Ab) as a potential treatment for these pathologies in a spontaneous model of CNV in JR5558 mice. We administered anti-VEGF, anti-ANG-2, or anti-VEGF/ANG-2 Abs, and measured CNV lesion number/size, vascular permeability, inflammatory cells and retinal apoptosis.
At postnatal day P45, animals were assigned to equimolar treatment groups: IgG control (10 mg/kg), anti-VEGF (5 mg/kg), anti-ANG-2 (5 mg/kg), or anti-VEGF/ANG-2 (10 mg/kg). Abs were dosed intraperitoneally at P46 and P53. Fluorescein angiography (FFA) and fluorophotometry data were collected at P60. At P61 animals were euthanized for tissue harvesting. Eyes were removed for wholemount TUNEL (retina) and Iba1 (RPE/choroid) staining. TUNEL was performed using a commercial kit for TdT-mediated dUTP-biotin nick end labeling, and Iba1 staining and isolectin B4 counterstain by immunohistochemistry, and quantified by semi-automated analysis. Lesion number/size were assessed in FFA images. Leakage was assessed by fluorophotometry. Statistics were done using one-way ANOVA and post-hoc tests.
There were significant reductions in lesion number/area with anti-VEGF, anti-ANG-2 and anti-VEGF/ANG-2 vs IgG control. There was a further therapeutic effect of anti-VEGF/ANG-2 on lesion area vs anti-VEGF and anti-ANG-2 monotherapy. Iba1 staining revealed reduced macrophages in the subretinal space with anti-VEGF, anti- ANG-2 and anti-VEGF/ANG-2 vs IgG, which was significant for anti-VEGF/ANG-2 only. TUNEL staining data showed that anti-ANG-2 and anti-VEGF/ANG-2 reduced retinal apoptotic nuclei, with the anti-VEGF/ANG-2 treatment showing highest significance (P = 0.011 for anti-ANG2, P = 0.007 for anti-VEGF/ANG-2).
Anti-VEGF/ANG-2 treatment resulted in superior reduction in FFA lesion area, reduced Iba1-positive subretinal macrophages, and decreased apoptosis at higher significance (up to 33%) vs IgG control compared to anti-VEGF or anti-ANG-2 monotherapy. Bispecific anti-VEGF/ANG-2 Ab gives superior efficacy on vascular, neuronal, and inflammatory readouts in JR5558 mice vs monotherapy. Anti-VEGF/ANG-2 is a promising therapy for wet AMD and DME.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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