Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea.
Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul 04763, Korea.
Clin Exp Immunol. 2023 Mar 8;211(1):31-45. doi: 10.1093/cei/uxac096.
Spleen tyrosine kinase (Syk) plays a pivotal role in the activation of B cells and innate inflammatory cells by transducing immune receptor-triggered signals. Dysregulated activity of Syk is implicated in the development of antibody-mediated autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis, but the effect of Syk inhibition on such diseases remains to be fully evaluated. We have developed a novel selective Syk inhibitor, SKI-O-592, and its orally bioavailable salt form, SKI-O-703 (cevidoplenib). To examine the efficacy of SKI-O-703 on the progression of SLE, New Zealand black/white mice at the autoimmunity-established phase were administrated orally with SKI-O-703 for 16 weeks. Levels of IgG autoantibody, proteinuria, and glomerulonephritis fell significantly, and this was associated with hypoactivation of follicular B cells via the germinal center. In a model of serum-transferred arthritis, SKI-O-703 significantly ameliorated synovitis, with fewer neutrophils and macrophages infiltrated into the synovial tissue. This effect was recapitulated when mice otherwise refractory to anti-TNF therapy were treated by TNF blockade combined with a suboptimal dose of SKI-O-703. These results demonstrate that the novel selective Syk inhibitor SKI-O-703 attenuates the progression of autoantibody-mediated autoimmune diseases by inhibiting both autoantibody-producing and autoantibody-sensing cells.
脾酪氨酸激酶（Syk）在通过转导免疫受体触发信号来激活 B 细胞和先天炎性细胞方面发挥着关键作用。Syk 活性失调与包括系统性红斑狼疮（SLE）和类风湿关节炎在内的抗体介导的自身免疫性疾病的发展有关，但 Syk 抑制对这些疾病的影响仍有待充分评估。我们开发了一种新型选择性 Syk 抑制剂 SKI-O-592 及其可口服生物利用的盐形式 SKI-O-703（cevidoplenib）。为了研究 SKI-O-703 对 SLE 进展的疗效，在自身免疫确立阶段，用 SKI-O-703 对新西兰黑/白小鼠进行口服治疗 16 周。IgG 自身抗体、蛋白尿和肾小球肾炎水平显著下降，这与生发中心滤泡 B 细胞的低激活有关。在血清转移关节炎模型中，SKI-O-703 显著改善了滑膜炎，滑膜组织中浸润的中性粒细胞和巨噬细胞减少。当用 TNF 阻断联合亚最佳剂量的 SKI-O-703 治疗对 TNF 治疗有抗性的小鼠时，观察到了这种效果。这些结果表明，新型选择性 Syk 抑制剂 SKI-O-703 通过抑制自身抗体产生细胞和自身抗体感应细胞来减轻抗体介导的自身免疫性疾病的进展。
