Pharmacological activation of LANCL2 ameliorates disease severity and decreases inflammation in a preclinical model of rheumatoid arthritis

Abstract. Lanthionine synthetase C-like 2 (LANCL2) is a novel immunoregulatory therapeutic target for the treatment of autoimmune diseases. Activation of LANCL2 enhances Treg responses through engagement of immunometabolic pathways and interactions with IL2/CD25 signaling, while downregulating effector cell subsets. An impaired Treg compartment has been proposed as one of the key contributors to the pathogenesis of rheumatoid arthritis (RA). We have developed NIM-1324, an oral, once-daily, highly systemically distributed small-molecule first-in-class therapeutic that selectively activates LANCL2 with a benign safety profile. We evaluated the therapeutic efficacy of oral NIM-1324 in a collagen-induced arthritis (CIA) mouse model of RA. Oral daily treatment with NIM-1324 significantly reduced disease activity, including paw redness and swelling, and pathology compared to the vehicle group. Furthermore, activation of LANCL2 by NIM-1324 decreased systemic inflammation, reducing IL-17+ and IL-21+ CD4+ T cells plus TNF-producing myeloid cells while the Tregs compartment was enhanced. LANCL2 deficiency in mice resulted in increased disease severity, inflammatory pathology and frequency of inflammatory subsets, including Th17 and Th1 cells. In human peripheral blood mononuclear cells, NIM-1324 decreased secretion of inflammatory mediators. This data supports that the pharmacological activation of LANCL2 by NIM-1324 is a promising therapeutic approach for the treatment of RA.