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Gemmy Chui Ming Cheung, Veluchamy A Barathi, Bo Bo Tun, Say Wei Yeo, Pei Pei Gan, Chan lwin Nyein, Jorg Regula, Guido Hartman; Dual inhibition of angiopoietin-2 and vascular endothelial growth factor-A with Crossmab RG7716 suppressed laser-induced choroidal neovascularization in a non-human primate model. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1174.
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RG7716 is a bispecific antibody developed with CrossMab technology to tightly bind VEGF-A on one arm and angiopoietin (Ang)-2 on the other arm. We evaluated in vivo efficacy of RG7716 in a nonhuman primate model of laser-induced choroidal neovascularization (CNV).
CNV was induced by laser photocoagulation on Day 0 in both eyes of 30 cynomolgus monkeys. Laser-induced lesions were confirmed; their severity was scored using fluorescein angiography from grade 1 (no hyperfluorescence) to grade 4 (bright hyperfluorescence and leakage) by a masked investigator on Day 14. Intravitreal injection was administered in both eyes on Day 15. Three active-treatment groups (high-dose RG7716, 90ug/0.05mL; low-dose RG7716, 30ug/0.05mL; and anti-Ang-2, 90ug/0.05mL), one active control group (anti-VEGF-A [ranibizumab, the best characterized anti-VEGF inhibitor], 30ug/0.05mL, equimolar to high-dose RG7716), and one inactive control group (isotype at 90ug/0.05mL) were included. Change in CNV grade was determined by comparing fluorescein angiography on Days 28 vs 14. Aqueous humor was collected from all eyes at baseline and on Days 15 and 32. Cytokine analysis of aqueous was performed by Multiplex ELISA system measuring IL-6, IL-8, MCP1, VEGF-A, PDGF-B, Ang-2 and bFGF.
A single intravitreal injection of high- and low-dose RG7716 reduced mean CNV lesion grade by 0.99-fold and -0.68 fold respectively. Treatment with anti-VEGF-A (Ranibizumab) resulted in reduction of mean CNV lesion grade by 0.63-fold. anti ANG2 treatment results in a reduction of mean CNV lesion grade by -0.46 -fold. At an equimolar number of binding sites, RG7716 reduced lesion severity significantly more than anti-VEGF alone (analysis of variance followed by Tukey’s multiple comparison, P<0.05). Ang-2 and VEGF levels were significantly downregulated by RG7716, as were the proinflammatory cytokines IL-6, IL-8, and MCP-1.
Dual inhibition of ANG-2 and VEGF-A resulted in the suppression of pre-formed laser-induced CNV in the non-human primate model. . Due to the suppression of CNV formation and reduction of inflammation as measured by cytokines in aqueous humor, RG7716 may be a feasible treatment for CNV associated with age-related macular degeneration or other causes.
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