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

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.