What does this research mean for the field?

Dual inhibition of Ang-2 and VEGF-A provides superior and complementary anti-inflammatory, anti-leakage, and neuroprotective effects in retinal disease models compared to single inhibition, suggesting a mechanism for its clinical efficacy. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

June 12, 2023Open Access

Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion

Structured PICO

Does dual Ang-2/VEGF-A inhibition reduce neovascularization, vascular leakage, and inflammation in mouse models of retinal pathology?

Population

JR5558 mice (4-5 weeks old, male and female) with spontaneous choroidal neovascularization (sCNV) and C57BL/6J mice (10-11 weeks old, male) with retinal ischemia/reperfusion (I/R) injuries.

Intervention

Bi-specific anti-Ang-2/anti-VEGF-A antibody (10 mg/kg intraperitoneal for sCNV model; 3 µg/µL intravitreal for I/R model), anti-Ang-2 antibody alone, or anti-VEGF-A antibody alone.

Comparator

IgG control antibody (10 mg/kg intraperitoneal or 3 µg/µL intravitreal) or untreated.

Outcome

Choroidal neovascularization (CNV) area, neovascular leakage, and macrophage/microglia accumulation at 1 and 5 weeks (sCNV model); retinal vascular leakage and neurodegeneration at 48 hours (I/R model).surrogate

Dual Ang-2/VEGF-A inhibition provides complementary anti-inflammatory and neuroprotective effects in retinal disease models, supporting the mechanism of action for faricimab.

Abstract

Introduction: Clinical trials demonstrated that co-targeting angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF-A) with faricimab controls anatomic outcomes and maintains vision improvements, with strong durability, through 2 years in patients with neovascular age-related macular degeneration and diabetic macular edema. The mechanism(s) underlying these findings is incompletely understood and the specific role that Ang-2 inhibition plays requires further investigation. Methods: We examined the effects of single and dual Ang-2/VEGF-A inhibition in diseased vasculatures of JR5558 mice with spontaneous choroidal neovascularization (CNV) and in mice with retinal ischemia/reperfusion (I/R) injuries. Results: In JR5558 mice, Ang-2, VEGF-A, and dual Ang-2/VEGF-A inhibition reduced CNV area after 1 week; only dual Ang-2/VEGF-A inhibition decreased neovascular leakage. Only Ang-2 and dual Ang-2/VEGF-A inhibition maintained reductions after 5 weeks. Dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 1 week. Both Ang-2 and dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 5 weeks. In the retinal I/R injury model, dual Ang-2/VEGF-A inhibition was statistically significantly more effective than Ang-2 or VEGF-A inhibition alone in preventing retinal vascular leakage and neurodegeneration. Discussion: These data highlight the role of Ang-2 in dual Ang-2/VEGF-A inhibition and indicate that dual inhibition has complementary anti-inflammatory and neuroprotective effects, suggesting a mechanism for the durability and efficacy of faricimab in clinical trials.

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