Amiselimod (MT-1303), a Novel Sphingosine 1-Phosphate Receptor-1 Modulator, Potently Inhibits the Progression of Lupus Nephritis in Two Murine SLE Models

Abstract

Amiselimod (MT-1303) is a novel and selective sphingosine 1-phosphate receptor-1 (S1P1) modulator with a more favorable cardiac safety profile than other S1P1 receptor modulators. In this study, we evaluated the effects of MT-1303 on the progression of lupus nephritis in two well-known murine systemic lupus erythematosus (SLE) models, MRL/lpr and NZBWF1 mice, compared with those of FK506. Daily oral doses of 0.1 and 0.3 mg/kg MT-1303 not only inhibited the development of lupus nephritis when administered before onset in MRL/lpr and NZBWF1 mice but also improved symptoms of lupus nephritis when administered after onset in MRL/lpr mice. Its efficacy in these models was more potent or comparable to that of FK506 (1 and 3 mg/kg). In histological analysis, treatment with MT-1303 inhibited infiltration of T cells into the kidneys, mesangial expansion, and glomerular sclerosis. MT-1303 treatment resulted in a marked reduction in T cells and B cells in the peripheral blood and significantly inhibited increases in the number of plasma cells in the spleen and T cells in the kidneys. In addition, administration of MT-1303 suppressed elevations in serum anti-dsDNA antibody levels in MRL/lpr mice, but not in NZBWF1 mice. Our findings show that MT-1303 exhibits marked therapeutic effects on lupus nephritis in two SLE models, likely by reducing the infiltration of autoreactive T cells into the kidneys. These results suggest that MT-1303 has the potential to be used as a therapeutic agent for patients suffering from SLE, including lupus nephritis.

Amiselimod, a sphingosine 1-phosphate receptor-1 modulator, for systemic lupus erythematosus: A multicenter, open-label exploratory study

“…Amiselimod (MT-1303), an oral selective S1P 1 receptor modulator, is converted in vivo to its active metabolite, amiselimod phosphate (amiselimod-P), 16 and has a more favorable cardiac safety profile than fingolimod. 17 Our previous findings confirmed that amiselimod inhibits lupus nephritis progression in MRL/lpr and NZBWF1 mice, 18 suggesting its potential effectiveness in the treatment of SLE in humans.…”

“…32 The effects of amiselimod on blood anti-ds-DNA antibody levels in SLE animal models of SLE were contradictory. 18 Administration of amiselimod suppressed the increase in anti-dsDNA antibody levels in MRL/ lpr but not NZBWF1 mice. However, these results are consistent with those observed with other S1P 1 receptor modulators in MRL/ lpr and NZBWF1 mice.…”

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

“…Amiselimod/MT-1303 is an oral prodrug that is converted to its active metabolite (MT-1303-P) by sphingosine kinases (SphKs); it has been evaluated for various immune-mediated diseases such as MS, SLE, IBD, and psoriasis [ 37 , 74 – 77 ]. Amiselimod has a higher affinity for S1PR1 than for S1PR2–5, obtaining a more favorable cardiac safety profile than non-selective S1PRs modulators [ 78 ].…”

“…Regarding infections, research reveals that only specific subsets are affected, such as T (CD3) and B (CD20) lymphocytes [ 131 , 132 ], whereas natural killer, NKT, granulocyte, and monocyte counts should be not affected, maintaining immune surveillance against cancer and viral infections [ 39 , 134 , 135 ]. Table 2 compares features of S1PR modulators mentioned in this review [ 4 , 39 , 58 , 72 , 74 , 101 , 130 , 133 – 138 ].…”

“…Table 2 compares features of S1PR modulators mentioned in this review [ 4 , 39 , 58 , 72 , 74 , 101 , 130 , 133 – 138 ].…”