Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
Department of Orthopedics, Rheumatology, and Traumatology, School of Medical Science, University of Campinas (UNICAMP), Campinas, 13083-887 São Paulo, Brazil.
Cell Rep Med. 2023 May 16;4(5):101036. doi: 10.1016/j.xcrm.2023.101036.
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.
遗传和体内证据表明，Toll 样受体（TLR）7 和 8 异常识别含 RNA 的自身抗原会导致自身免疫性疾病。在这里，我们报告了 MHV370 的临床前特征，这是一种选择性口服 TLR7/8 抑制剂。体外实验中，MHV370 抑制了人源和鼠源细胞中 TLR7/8 依赖性细胞因子的产生，特别是干扰素-α，这是一种经临床验证的自身免疫性疾病驱动因子。此外，MHV370 还阻断了 TLR7/8 下游的 B 细胞、浆细胞样树突状细胞、单核细胞和中性粒细胞反应。在体内，MHV370 的预防性或治疗性给药可阻断 TLR7 反应的分泌，包括细胞因子分泌、B 细胞激活以及干扰素刺激基因的表达等。在狼疮的 NZB/W F1 小鼠模型中，MHV370 可阻止疾病进展。与羟氯喹不同，MHV370 可有效阻断来自系统性红斑狼疮患者血清的特定免疫复合物触发的干扰素反应，这表明它与临床标准治疗有所区别。这些数据支持将 MHV370 推进到正在进行的 2 期临床试验。
