Abstract
Purpose :
Corticosteroids are the standard of care for use in local therapy for patients with uveitis. While effective, they have serious risks including cataracts and glaucoma. An alternative local agent that is safe and effective would be a significant advance. ALPN-101 is an Fc fusion protein of a human inducible T cell costimulator ligand (ICOSL) variant immunoglobulin domain (vIgDTM) designed to simultaneously inhibit the CD28 and ICOS costimulatory pathways. ALPN-101 has demonstrated efficacy in multiple inflammatory disease models. We report here the results of a study testing the efficacy of local administration of ALPN-101 in experimental autoimmune uveitis (EAU).
Methods :
EAU was induced on Study Day (SD) 0 in Lewis rats using IRBP peptide R16 in complete Freund’s adjuvant. Rats were treated (n=4/group) with ALPN-101 (80 µg), Fc control (40 µg), PBS, or triamcinolone acetonide (steroid) (100 µg) by intravitreal injection into the right eye on SD10 & 12. An additional group was treated with ALPN-101 on SD8 &10. Unmasked clinical scores were obtained on SD0 & SD7-14. Optical coherence tomography (OCT) images were obtained on SD7, 11, & 14. On SD14, eyes were collected for histology. OCT images and histologic sections were scored by masked graders. Median score of treated eyes from each group were compared by Kruskal-Wallis with uncorrected Dunn’s test.
Results :
Compared to controls, ALPN-101 demonstrated significant suppression of inflammation (*p<0.05, **p<0.01), as assessed by SD14 unmasked clinical score (median; PBS, 3.5; Fc, 3.5; ALPN-101 SD8/10, 0.75*; ALPN-101 SD10/12, 1.5*; steroid, 0**) masked OCT score (median; PBS, 2; Fc, 2.5; ALPN-101 SD8/10, 0*; ALPN-101 SD10/12, 1.5; steroid, 0.5*), and histology (median; PBS, 2.5; Fc, 3; ALPN-101 SD8/10, 0.75*; ALPN-101 SD10/12, 2; steroid, 0.5**) (Fig. 1). Significant weight loss occurred in the steroid treated animals (mean weight change= -12.7%), but not in the ALPN-101 (+3%) or control animals (+2%).
Conclusions :
Local treatment with the dual CD28/ICOS antagonist ALPN-101 effectively suppresses EAU in Lewis rats. Furthermore, intravitreal injection of ALPN-101 was well-tolerated without the weight loss noted with steroid treatment. Additional studies will be needed to evaluate ocular risks of therapy. ALPN-101 may be a safe and effective alternative to steroids for use in local treatment of uveitis.
This is a 2020 ARVO Annual Meeting abstract.