Zhang Ning, Zhang Changqing, Zeng Zhihong, Zhang Jiyong, Du Shengnan, Bao Chunde, Wang Zhe
Longwood Biopharmaceuticals, Shanghai, People's Republic of China.
Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, People's Republic of China.
J Inflamm Res. 2021 May 21;14:2133-2147. doi: 10.2147/JIR.S301076. eCollection 2021.
Research on JAK family members as therapeutic targets for autoimmune diseases has brought tofacitinib and baricitinib into clinical for the treatment of rheumatoid arthritis and other autoimmune diseases. Despite the potent efficacy of these first-generation JAK inhibitors, their broad-spectrum JAK inhibition and adverse events warrant development of a JAK1-specific inhibitor to improve their safety profile.
In this study, we characterized a JAK1-specific inhibitor, LW402, on biochemical and human whole-blood assays. We further evaluated the therapeutic efficacy of LW402 in a rat adjuvant-induced arthritis (rAIA) model and a mouse collagen-induced arthritis (mCIA) model. The safety of LW402 was evaluated in both SpragueDawley rats and cynomolgus monkeys.
LW402 exhibited potent nanomolar activity against JAK1 and showed a 45-fold selectivity for inhibition of JAK1- over JAK2-dependent signaling induced by either IL6 or GM-CSF in human whole-blood assays. In the rAIA model, oral dosing of LW402 resulted in a dose-dependent improvement in disease symptoms, including reduction in paw swelling, marked reduction in the inflammatory-cell infiltration to synovial tissue, and protection of articular cartilage and bone from damage. The therapeutic efficacy of LW402 correlated well with the plasma exposure of LW402 and the extent of pSTAT3 inhibition in white blood cells. LW402 also effectively eased disease symptoms in the mCIA model. Toxicity studies in the Sprague Dawley rats and cynomolgus monkeys established a ≥5x therapeutic window for LW402 as drug exposures of toxicity study NOAEL dose and pharmacology study ED dose were compared.
We developed a novel JAK1-specific inhibitor LW402 with potent efficacy in rAIA and mCIA models. We established a good safety profile for LW402 in toxicity studies, and the overall superiority of LW402 should translated well to the clinical setting for the treatment of RA and other autoimmune diseases.
将JAK家族成员作为自身免疫性疾病治疗靶点的研究已使托法替布和巴瑞替尼进入临床，用于治疗类风湿关节炎和其他自身免疫性疾病。尽管这些第一代JAK抑制剂疗效显著，但其广谱JAK抑制作用及不良事件促使人们研发JAK1特异性抑制剂以改善其安全性。
在本研究中，我们在生化和人全血试验中对JAK1特异性抑制剂LW402进行了特性分析。我们进一步在大鼠佐剂性关节炎（rAIA）模型和小鼠胶原诱导性关节炎（mCIA）模型中评估了LW402的治疗效果。在Sprague-Dawley大鼠和食蟹猴中评估了LW402的安全性。
LW402对JAK1表现出强效的纳摩尔活性，在人全血试验中，其对JAK1的抑制选择性比对IL6或GM-CSF诱导的JAK2依赖性信号传导高45倍。在rAIA模型中，口服LW402导致疾病症状呈剂量依赖性改善，包括爪肿胀减轻、滑膜组织炎症细胞浸润明显减少以及关节软骨和骨骼免受损伤。LW402的治疗效果与LW402的血浆暴露量以及白细胞中pSTAT3的抑制程度密切相关。LW402在mCIA模型中也有效缓解了疾病症状。通过比较毒性研究的无观察到不良反应水平（NOAEL）剂量和药理学研究的有效剂量（ED）的药物暴露量，在Sprague Dawley大鼠和食蟹猴中进行的毒性研究确定了LW402的治疗窗≥5倍。
我们研发了一种新型JAK1特异性抑制剂LW402，在rAIA和mCIA模型中具有强效疗效。我们在毒性研究中确定了LW402良好的安全性，LW402的总体优势应能很好地转化至类风湿关节炎和其他自身免疫性疾病的临床治疗中。
Zotero 插件