Preclinical characterization of the Toll-like receptor 7/8 antagonist MHV370 for lupus therapy

Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by Toll-like receptors (TLRs) 7 and 8 drives autoimmune diseases. Here we report on the preclinical characterization of MHV370, a selective oral TLR7/8 inhibitor. In vitro, MHV370 inhibits TLR7/8-dependent production of cyto-kines in human and mouse cells, notably interferon-a, a clinically validated driver of autoimmune diseases. Moreover, MHV370 abrogates B cell, plasmacytoid dendritic cell, monocyte, and neutrophil responses downstream of TLR7/8. In vivo, prophylactic or therapeutic administration of MHV370 blocks secretion of TLR7 responses, including cytokine secretion, B cell activation, and gene expression of, e.g., interferon -stim-ulated genes. In the NZB/W F1 mouse model of lupus, MHV370 halts disease. Unlike hydroxychloroquine, MHV370 potently blocks interferon responses triggered by specific immune complexes from systemic lupus erythematosus patient sera, suggesting differentiation from clinical standard of care. These data support advancement of MHV370 to an ongoing phase 2 clinical trial.

Automated summary

Genetic and in vivo evidence suggests that MHV370, a selective oral TLR7/8 inhibitor, can effectively inhibit TLR7/8-dependent immune cell activity and cytokine production, particularly interferon-a. In mouse models, MHV370 shows promising results in preventing and treating TLR7 responses-related diseases, including cytokine secretion, B cell activation, and upregulation of interferon-stimulated genes. These findings support the ongoing phase 2 clinical trial of MHV370.