Milici Anthony J, Kudlacz Elizabeth M, Audoly Laurent, Zwillich Samuel, Changelian Paul
Pfizer Global Research and Development, MS#8220-2235, Groton, CT 06340, USA.
Arthritis Res Ther. 2008;10(1):R14. doi: 10.1186/ar2365. Epub 2008 Jan 30.
CP-690550 is a small molecule inhibitor of Janus kinase 3 (JAK3), a critical enzyme in the signaling pathway of multiple cytokines (interleukin (IL)-2, -7, -15 and -21) that are important in various T cell functions including development, activation and homeostasis. The purpose of this study was to evaluate CP-690550 in murine collagen-induced (CIA) and rat adjuvant-induced (AA) models of rheumatoid arthritis (RA).
CIA and AA were induced using standard protocols and animals received the JAK3 inhibitor via osmotic mini-pump infusion at doses ranging from 1.5-15 mg/kg/day following disease induction. Arthritis was assessed by clinical scores in the CIA models and paw swelling monitored using a plethysmometer in the AA model until study conclusion, at which time animals were killed and evaluated histologically.
CP-690550 dose-dependently decreased endpoints of disease in both RA models with greater than 90% reduction observed at the highest administered dose. An approximate ED50 of approximately 1.5 mg/kg/day was determined for the compound based upon disease endpoints in both RA models examined and corresponds to CP-690550 serum levels of 5.8 ng/ml in mice (day 28) and 24 ng/ml in rats (day 24). The compound also reduced inflammatory cell influx and joint damage as measured histologically. Animals receiving a CP-690550 dose of 15 mg/k/d showed no histological evidence of disease.
The efficacy observed with CP-690550 in CIA and AA suggests JAK3 inhibition may represent a novel therapeutic target for the treatment of RA.
CP - 690550是一种Janus激酶3(JAK3)的小分子抑制剂,JAK3是多种细胞因子(白细胞介素(IL) - 2、 - 7、 - 15和 - 21)信号通路中的关键酶,这些细胞因子在包括发育、激活和稳态在内的各种T细胞功能中起着重要作用。本研究的目的是在小鼠胶原诱导性关节炎(CIA)和大鼠佐剂诱导性关节炎(AA)的类风湿关节炎(RA)模型中评估CP - 690550。
采用标准方案诱导CIA和AA,疾病诱导后,动物通过渗透微型泵输注接受JAK3抑制剂,剂量范围为1.5 - 15mg/kg/天。在CIA模型中通过临床评分评估关节炎,在AA模型中使用体积描记器监测爪肿胀,直至研究结束,此时处死动物并进行组织学评估。
在两种RA模型中,CP - 690550均剂量依赖性地降低疾病终点,在最高给药剂量下观察到超过90%的降低。根据所检测的两种RA模型中的疾病终点,确定该化合物的近似半数有效剂量(ED50)约为1.5mg/kg/天,这相当于小鼠(第28天)血清中CP - 690550水平为5.8ng/ml,大鼠(第24天)为24ng/ml。该化合物还减少了组织学测量的炎性细胞浸润和关节损伤。接受15mg/k/d剂量CP - 690550的动物未显示疾病的组织学证据。
在CIA和AA模型中观察到的CP - 690550的疗效表明,抑制JAK3可能代表治疗RA的一种新的治疗靶点。