Abstract
Purpose :
Recent Phase 2a clinical studies were completed with AKST4290, a potent CCR3 inhibitor, in treatment- naïve nAMD and refractory nAMD patients. The majority (83%) of nAMD subjects demonstrated stable or improved best-corrected visual acuity after 6 weeks of AKST4290 treatment. Preclinical studies were subsequently conducted to examine whether the efficacy observed in nAMD patients was in part due to blocking CCR3-mediated retinal homing of damage-promoting immune cells from the periphery which in turn dampens local inflammation and may subsequently modify disease progression.
Methods :
The sodium iodate (NaIO3) model (single iv injection, 20 mg/kg) was used to induce retinal inflammation and degeneration in C57Bl6 mouse eyes. Mice were treated with twice daily oral dose (60 mg/kg) of AKST4290. Flow cytometry was used to examine the immune cell composition in the retinal pigment epithelium (RPE) at 3 days post NaIO3 injection. The effect of AKST4290 treatment on inflammatory cytokines in the eye was probed using Luminex immunoassays. Nested generalized linear model with pair wise comparison was used for statistical analysis.
Results :
NaIO3 induced a significant increase in number of immune cells in the degenerating RPE (Control vs NaIO3; monocytes [cell counts, mean±sem]: 74±16 vs 1679±222; neutrophil: 14±3 vs 146±17; CD4 T cells: 33±5 vs 170±26; p<<0.01). AKST4290 treatment significantly reduced immune cell infiltration in NaIO3 damaged RPE (NaIO3+4290; monocytes: 1051±153; neutrophil: 82±15; CD4 T cells: 131±29; NaIO3 vs NaIO3+4290 p<0.01). Treatment with AKST4290 also significantly reduced NaIO3 induced increase in chemokines CCL5 (Control vs NaIO3 vs NaIO3+4290 (mean±sem (pg/ml): 1.41±0.11 vs 2.05±0.13 vs 1.76±0.13, p<0.05) and CXCL9 (1.8±0.26 vs 5.56±0.67 vs 3.67±0.43, p<0.05).
Conclusions :
These data demonstrate that systemic inhibition of CCR3 by AKST4290 reduces the accumulation of peripheral immune cells in the RPE, which is the primary injury site in the NaIO3 model and in nAMD. This reduction in recruitment of immune cells was associated with a decrease in chemokines in the degenerating RPE. These findings help illustrate the mechanism of action for AKST4290, supporting its observed efficacy as a drug candidate in clinical trials of nAMD patients.
This is a 2021 ARVO Annual Meeting abstract.