BT-11 (omilancor), a first-in-class, topical therapeutic for psoriasis, ameliorates disease severity and inflammation through activation of LANCL2 pathway

Abstract

Abstract BT-11 (omilancor) is a small molecule therapeutic that activates the LANCL2 pathway in immune and epithelial cells, resulting in regulatory effects at the intersection of immunity and metabolism. LANCL2 modulates the plasticity between Th17 and regulatory T cells (Tregs), favoring the stability and suppressive capacity of Tregs. Given the implication of the LANCL2 pathway in autoimmune disease and the demonstrated clinical efficacy and safety of BT-11 in a Phase 2 clinical trial of UC, we evaluated the therapeutic efficacy of BT-11 in psoriasis. In an imiquimod-induced mouse model of psoriasis, pharmacological activation of LANCL2 through topical BT-11 treatment ameliorates disease severity, resulting in over 60% reduction of PASI score. Indeed, BT-11 treatment decreased acanthosis and immune cell infiltration, with no signs of parakeratosis. The loss of LANCL2 in mice resulted in increased hyperkeratosis and parakeratosis. Local LANCL2 activation by BT-11 resulted in decreased TNF, IL17, IL6 and IL21-producing cells in the spleen. Additionally, LANCL2 activation regulated keratinocyte metabolism and function. Keratinocytes from BT-11-treated mice presented lower metabolic activation, reported as decreased ATP production, mitochondrial respiration and glucose metabolism. In translational studies with human PBMCs, BT-11 modulated the metabolic profile of CD4+ T cells at late state glycolysis, favoring oxidative pathways, and decreased expression of proinflammatory cytokines (IFNγ, TNFα), while upregulating IL-10. These results merit further exploration into the implication of LANCL2 signaling in human psoriasis and leverages the development of BT-11, as a first-in-class, topical therapeutic for psoriasis.