Preclinical characterization of the Toll-like receptor 7/8 antagonist MHV370 for lupus therapy.
Toll-like receptors
antagonist
autoimmunity
innate immunity
lupus
pharmacology
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
16 05 2023
16 05 2023
Historique:
received:
21
09
2022
revised:
17
11
2022
accepted:
12
04
2023
medline:
19
5
2023
pubmed:
18
5
2023
entrez:
17
5
2023
Statut:
ppublish
Résumé
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 cytokines in human and mouse cells, notably interferon-α, 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-stimulated 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.
Identifiants
pubmed: 37196635
pii: S2666-3791(23)00150-7
doi: 10.1016/j.xcrm.2023.101036
pmc: PMC10213863
pii:
doi:
Substances chimiques
Toll-Like Receptor 7
0
Hydroxychloroquine
4QWG6N8QKH
Interferons
9008-11-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101036Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests All authors except S.A., B.B., H.I.B., J.D., D.K., P.M., F.R., and J.S.R. are current employees and shareholders of Novartis Pharma AG. MHV370 is described in patent WO2018047081.
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