Efficacy of a CCR2 Antagonist for Treating Choroidal Neovascularization

Abstract

 

Purpose:

 

MCP-1 (monocyte chemotactic protein-1) and its receptor, CCR2, play a major role for infiltration of macrophages. To investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV).

 

Methods:

 

INCB3344 of 1.8uM was intravitreally injected to a laser induced CNV mouse model (n=81 spots), followed by evaluation of CNV size and macrophage infiltration on retinal pigment epithelium (RPE)-choroid flat mounts. Expression of vascular endothelial growth factor (VEGF) and phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) was examined by immunohistochemistry, ELISA, real-time PCR or Western blot analysis. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice (n=6) by fundus photography and fluorescence angiography.

 

Results:

 

Intravitreal injection of 1.8uM INCB3344 significantly reduced the mean CNV area (19,759.5 ±861.1µm² vs 11,392.2 ±468.8µm², P<0.001) and VEGF expression in the choroid-RPE complex (289.3±27.8pg/mg vs 199.1±8.2pg/mg, P=0.012). INCB3344 treatment significantly inhibited macrophage infiltration into the laser-irradiated area (p<0.001), and VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1–/– mice regressed by 70.35% in INCB3344-treated animals (Fig) while no change was detected in vehicle-treated control mice (p<0.001).

 

Conclusions:

 

INCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration.  

 

Keywords: age-related macular degeneration • choroid: neovascularization • inflammation