EQ504: A Novel AhR Modulator That Promotes Immune Tolerance Through Il-10 and Il-22 Cytokine Release 2309955

Abstract

Abstract Introduction The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that promotes immune tolerance in part by enhancing regulatory T cell (Treg) development and function of macrophages. Despite its therapeutic potential inflammatory bowel disease (IBD), clinical development of AhR modulators has been limited by the lack of potent, selective and drug-like molecules. Methods We evaluated EQ504, a novel small-molecule AhR modulator derived from the endogenous ligand ITE and obefazimod, a clinically validated molecule in IBD. Human immune cells were treated with each compound to assess AhR activation, regulatory T cell differentiation, and macrophage polarization. Cytokine production and phenotypic markers were analyzed to define immunoregulatory outcomes. Results EQ504 activated AhR in both Tregs and monocytes/macrophages. The two molecules drove distinct regulatory T cell programs: EQ504 preferentially induced FOXP3⁻ Type 1 regulatory T cells (Tr1s), whereas obefazimod promoted FOXP3+ Treg differentiation. Tr1 cells are particularly relevant in IBD due to their IL-10—mediated immunosuppression, granzyme B—dependent targeting of inflammatory antigen-presenting cells, and capacity to restrain Th1/Th17-driven inflammation while supporting mucosal repair. EQ504 also shifted macrophage polarization toward an anti-inflammatory phenotype, decreasing M1 frequencies while increasing M2 frequencies, accompanied by reduced production of pro-inflammatory cytokines including IL-12p70, TNFα, IL-6, and IL-1β. Conclusion These findings identify EQ504 as a potent next generation AhR modulator with a unique immunoregulatory profile. EQ504 promotes Tr1mediated immune tolerance and anti-inflammatory macrophage polarization, mechanisms highly relevant to the treatment of IBD. Funding Source N/A Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)