Amiselimod (MT-1303), a novel sphingosine 1-phosphate receptor-1 functional antagonist, inhibits progress of chronic colitis induced by transfer of CD4+CD45RBhigh T cells

Abstract

Amiselimod (MT-1303) is a novel sphingosine 1-phosphate receptor-1 (S1P1 receptor) modulator with a more favorable cardiac safety profile than other S1P1 receptor modulators. MT-1303 phosphate (MT-1303-P), an active metabolite of MT-1303, exhibits S1P1 receptor agonism at a lower EC50 value than other S1P1 receptor modulators currently being developed. We aimed to evaluate the efficacy of MT-1303 and its mode of action in chronic colitis using an inflammatory bowel disease (IBD) model. Oral administration of MT-1303 (0.3 mg/kg) once daily for 3 days to mice almost completely abolished S1P1 receptor expression on CD4+ T cells from mesenteric lymph nodes, which corresponded to a marked decrease in CD4+ T cell count in peripheral blood, indicating that MT-1303-P acts as a functional antagonist of the S1P1 receptor. The potential benefit of MT-1303 for IBD was assessed using immunodeficient SCID mice with chronic colitis induced by adoptive transfer of CD4+CD45RBhigh T cells from BALB/c mice. An oral dose of 0.1 and 0.3 mg/kg MT-1303 administered daily one week after the cell transfer inhibited the development of chronic colitis with an efficacy comparable to that of an anti-mTNF-α mAb (250 μg/mouse). In addition, MT-1303 administration significantly reduced the number of infiltrating Th1 and Th17 cells into the lamina propria of the colon in colitis mice. Our results suggest that MT-1303 acts as a functional antagonist of the S1P1 receptor on lymphocytes, regulates lymphocyte trafficking, and inhibits infiltration of colitogenic Th1 and Th17 cells into the colon to inhibit the development of chronic colitis.

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

“…We have reported that fingolimod, the first S1P 1 receptor modulator, reduces infiltration of myelin antigen-specific Th17 and Th1 cells into the spinal cord [15]. Further, we have also confirmed that MT-1303 inhibits infiltration of colitogenic Th1 and Th17 cells into the colon in a mouse IBD model [30]. These results suggest that MT-1303 decreases infiltration of autoreactive Th1, Th17, and DN T cells into the kidneys by reducing the number of circulating lymphocytes in the blood, thereby eliciting a marked therapeutic effect on the progression of lupus nephritis in two SLE models.…”

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

“…In this regard, S1P 4 , as discussed previously in this review, is predominantly expressed in lymphoid tissues [88,95], and ligation and its subsequent signaling are involved in marking time regarding proliferation [286,287], a reduction of effector cytokines secreted [286,287], and migration of lymphocytes [288,289]. It is worth noting that amiselimod displays a very safe risk profile [290][291][292], while it is too early to consistently assess this for etrasimod [293]. Their application and/or investigation regarding their future therapeutic exploitability in neurological conditions should find due consideration soon.…”

Review article: the sphingosine 1 phosphate/sphingosine 1 phosphate receptor axis ‐ a unique therapeutic target in inflammatory bowel disease

“…The results demonstrated that amiselimod regulates lymphocyte trafficking, limits infiltration of colitogenic Th1 and Th17 cells into the colon, and inhibits the development of chronic colitis. 91 The investigation of the effects of amiselimod in moderate-to-severe, active Crohn's disease in a 14-week, randomised, placebo-controlled, phase II trial 92 with an open-label extension of ≥22 weeks 93 has been completed. However, amiselimod 0.4 mg/d for 12 weeks did not show a significant effect on clinical or biochemical disease activity in refractory Crohn's disease.…”