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

• DOI: 10.1016/j.xcrm.2023.101036
• Publication Date: 2023-05-16T14:36:01Z
• Authors: Stuart Hawtin; Cédric André; Géraldine Collign...; Simone Appenzeller; Bettina Bannert; Lea Baumgartner; Damian Beck; Claudia Betschart; Thomas Boulay; Hermine I. Brunner; Melanie Ceci; Jonathan Deane; Roland Feifel; Enrico Ferrero; Diego Kyburz; Frederique Lafossas; Pius Loetscher; Christina Merz-St...; Pierre Michellys; Barbara Nuesslein...; Friedrich Raulf; James S. Rush; Giulia Ruzzante; Thomas Stein; Samantha Zaharevitz; Grazyna Wieczorek; Richard Siegel; Peter Gergely; Tamas Shisha; Tobias Junt
• Keywords: Mice; Toll-Like Receptor 7; Humans; Animals; Lupus Erythematosus, Systemic; Interferons; Article; 3. Good health; Autoimmune Diseases; Hydroxychloroquine

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