Abstract
Purpose :
T cell costimulation has been implicated in the pathogenesis of autoimmune uveitis. Acazicolcept (ALPN-101) is an Fc fusion protein of the human inducible T cell costimulator ligand (ICOSL) and a variant immunoglobulin domain (vIgD™) designed to inhibit the CD28 and ICOS T cell costimulatory pathways. Here we evaluate the efficacy of systemic administration of acazicolcept in experimental autoimmune uveitis (EAU).
Methods :
EAU was induced on Study Day 0 (SD0) in female Lewis rats using IRBP peptide R16 in complete Freund’s adjuvant. Rats were treated with acazicolcept (100 mg/kg), an Fc control protein (50 mg/kg), or triamcinolone acetonide (0.8 mg/kg) once by subcutaneous injection on SD7. Masked clinical scores, body weights, and ocular histologies were assessed through SD14. Aqueous and intraocular contents collected on SD14 were analyzed by multiplex cytokine analysis and flow cytometry.
Results :
Compared to Fc control, acazicolcept significantly reduced the number of eye-infiltrating CD45+ cells and IL-17A+ and IFNγ+ CD3+ T cells and tended to decrease intraocular aqueous cytokines including leptin, IL-1β, RANTES, IFNγ, IL-17A, VEGF, CXCL5, and IP-10, as effectively as steroid treatment (though not always statistically significantly). From SD10-13, Fc control-treated rats demonstrated a significantly higher average masked clinical score than the steroid or acazicolcept-treated groups (AUC, p<0.01). Histology scores of eyes from steroid- (4.7 ± 4.9, p<0.05) or acazicolcept-treated rats (4.2 ± 5.2, p<0.05) were also significantly lower than Fc-treated rats (19.1 ± 10.39) on SD14. Steroid-treated animals lost a significant amount of body weight during treatment between SD7-14, as compared to acazicolcept- (p=0.0003) or Fc control-treated (p=0.0071) animals.
Conclusions :
Systemic treatment with acazicolcept significantly suppresses EAU in rats, as evidenced by reduced clinical and histological scores, and correlated with reduced eye-infiltrating IL-17A+ and IFNγ+ T cells. Acazicolcept was well-tolerated without the weight loss induced by steroid treatment. Due to species- and disease-related differences, the dose regimen used in this study is not predictive of the effective dose in humans. However, these data suggest acazicolcept may be a safe and effective alternative to corticosteroids for use in treatment of autoimmune uveitis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.