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Published on: July 26, 2017
Preclinical characterization of the Toll-like receptor 7/8 antagonist MHV370 for lupus therapy
Stuart Hawtin1, Cédric André1, Géraldine Collignon-Zipfel1
1Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
Abstract:
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.
Insights
A new drug, MHV370, selectively inhibits Toll-like receptors 7 and 8 (TLR7/8), crucial in autoimmune diseases. Preclinical studies show it halts lupus progression and blocks key inflammatory responses, supporting its clinical development.
Area of Science:
- Immunology
- Pharmacology
- Rheumatology
Background:
- Aberrant recognition of RNA autoantigens by Toll-like receptors (TLRs) 7 and 8 is implicated in autoimmune disease pathogenesis.
- Interferon-alpha (IFN-α) is a key cytokine driving autoimmune conditions.
Purpose of the Study:
- To characterize MHV370, a novel, selective oral inhibitor of TLR7/8, for preclinical efficacy.
- To evaluate MHV370's potential as a therapeutic agent for autoimmune diseases.
Main Methods:
- In vitro assessment of MHV370's inhibition of TLR7/8-dependent cytokine production in human and mouse cells.
- In vivo studies in the NZB/W F1 mouse model of lupus to evaluate prophylactic and therapeutic effects.
- Comparison of MHV370's efficacy against hydroxychloroquine in blocking immune complex-triggered interferon responses.
Main Results:
- MHV370 demonstrated potent inhibition of TLR7/8-mediated cytokine production, including IFN-α.
- The inhibitor abrogated B cell, plasmacytoid dendritic cell, monocyte, and neutrophil responses.
- In vivo, MHV370 blocked TLR7 responses, halted lupus progression in mice, and effectively inhibited interferon responses triggered by patient immune complexes.
Conclusions:
- MHV370 is a potent and selective oral TLR7/8 inhibitor with promising preclinical data.
- MHV370 demonstrates efficacy in a lupus model and differentiates from current standards of care.
- These findings support the advancement of MHV370 into phase 2 clinical trials for autoimmune diseases.
