赢迪文献分享 | JAK抑制剂与移植物抗宿主病(GVHD)的治疗

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赢迪文献分享 | JAK抑制剂与移植物抗宿主病(GVHD)的治疗

日期:2020-08-14 / 人气:

JAK是一个在细胞内部广泛存在的与细胞因子受体相关的蛋白。上世纪90年代,以傅新元教授为代表的研究者阐明了整个JAK-STAT信号转导通路机制,为后续JAK抑制剂的开发奠定了基础。JAK-STAT通路主要与I/II类细胞因子相关,包括白介素、干扰素、GM-CSF、促红细胞生成素等,与机体免疫、血液细胞发育等密切相关。目前一共发现4种JAK蛋白,分别是JAK1、JAK2、JAK3和TYK2,但JAK蛋白和细胞因子之间并不是一一对应的。所以无论是非选择性的泛JAK抑制剂,还是选择性高的特异性JAK抑制剂,都会影响多种细胞因子的信号传递。

 

目前已上市7种JAK抑制剂,第一代JAK抑制剂包括芦可替尼、托法替尼、巴瑞克替尼,都是选择性较低的泛JAK抑制剂,对多种JAK蛋白都有较强的抑制作用。而后面上市的JAK抑制剂则以高选择性的特异性JAK抑制剂为主,更加针对性的抑制某一种JAK蛋白。目前已上市的JAK抑制剂大多都有较为明显的安全性问题,比如易出现血栓风险,被FDA在说明书上加了警示黑框。与第一代泛JAK抑制剂相比,高选择性JAK抑制剂在降低毒性方面具有优势;但在某些情况下,注重选择性可能导致效力降低。

 

移植物抗宿主病(GVHD)是由于移植后异体供者移植物中的免疫细胞,以受者靶细胞为目标发动的细胞毒攻击,其中皮肤、肝及肠道是主要的靶目标。特别是造血干细胞移植(HCT)后,中度(Ⅱ级)或重度(Ⅲ或Ⅳ级)急性GVHD的发生与生存率显著下降密切相关,所有接受异基因HCT患者均应接受急性GVHD的预防。现有的急性GVHD预防的标准方案是环孢素A(CsA)+短程甲氨蝶呤(MTX)方案,并根据不同的移植情况,添加霉酚酸酯(MMF)或抗胸腺细胞球蛋白(ATG)等。这些预防方案都能够有效的降低急性GVHD的发生率,但对病人的整体生存期提高有限。发生急性GVHD后的一线治疗药物是糖皮质激素,最常用甲泼尼龙,一旦糖皮质激素耐压或依赖后,就需要二线治疗药物,如甲氨蝶呤、巴利昔单抗、他克莫司、芦可替尼等。

 

2019年5月,美国FDA根据单臂II期REACH1研究的结果,批准了Incyte和诺华的JAK抑制剂芦可替尼用于12岁及以上儿童及成人患者,治疗类固醇难治性急性移植物抗宿主病(GvHD)。芦可替尼是首个也是唯一一个获FDA批准治疗类固醇难治性GvHD的药物。其II期临床REACH1及2个III期临床REACH2和REACH3均获得了成功,证明了JAK抑制剂在GVHD适应症的治疗潜力。但坏消息是,2020年1月Incyte宣布,其新一代JAK抑制剂Itacitinib治疗急性GVHD的三期临床未能达到主要终点,当天Incyte盘后股价应声下跌10%。更多关于JAK抑制剂和GVHD的研究进展,请看下面的视频。


 

 

 

 

参考资料:

1.Villarino, Alejandro V., et al. "SnapShot: Jak-STAT Signaling II." Cell 181.7 (2020): 1696-1696.

2.Schwartz, Daniella M., et al. "JAK inhibition as a therapeutic strategy for immune and inflammatory diseases." Nature Reviews Drug Discovery 16.12 (2017): 843-862.

3.Schwartz, Daniella M., et al. "Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases." Nature Reviews Rheumatology 12.1 (2016): 25.

4.O'Shea, John J., et al. "The JAK-STAT pathway: impact on human disease and therapeutic intervention." Annual review of medicine 66 (2015): 311-328.

5.Nan, Yuchen, Chunyan Wu, and Yan-Jin Zhang. "Interplay between Janus kinase/signal transducer and activator of transcription signaling activated by type I interferons and viral antagonism." Frontiers in immunology 8 (2017): 1758.

6.Lupardus, Patrick J., et al. "Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition." Proceedings of the National Academy of Sciences 111.22 (2014): 8025-8030.

7.Gadina, Massimo, et al. "Translating JAKs to Jakinibs." The Journal of Immunology 204.8 (2020): 2011-2020.

8.Chhabra, Saurabh, et al. "Comparative Analysis of Calcineurin Inhibitor–Based Methotrexate and Mycophenolate Mofetil–Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation." Biology of Blood and Marrow Transplantation 25.1 (2019): 73-85.

9.中国异基因造血干细胞移植治疗血液系统疾病专家共识(Ⅲ)— 急性移植物抗宿主病(2020 年版)

10.刘灿, and 刘启发. "白血病异基因造血干细胞移植后复发的预防." 中华血液学杂志 34.8(2013):729-732.

11.Kröger, Nicolaus, et al. "Antilymphocyte globulin for prevention of chronic graft-versus-host disease." New England Journal of Medicine 374.1 (2016): 43-53.

12.Bonifazi, Francesca, et al. "GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study." The Lancet Haematology 6.2 (2019): e89-e99.

13.Tang, Fei-Fei, et al. "Basiliximab as treatment for steroid-refractory acute graft-versus-host disease in pediatric patients after haploidentical hematopoietic stem cell transplantation." Biology of Blood and Marrow Transplantation 26.2 (2020): 351-357.

14.Wang, Y., et al. "Low-dose MTX combined with low-dose methylprednisolone as a first-line therapy for the treatment of acute GVHD: safety and feasibility." Bone marrow transplantation 46.6 (2011): 892-898.

15.Jagasia, Madan, et al. "Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial." Blood, The Journal of the American Society of Hematology 135.20 (2020): 1739-1749.

16.Zeiser, Robert, et al. "Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease." New England Journal of Medicine 382.19 (2020): 1800-1810.

17.JAK抑制剂图鉴

18.JAK-STAT信号通路及JAK抑制剂

19.JAK抑制剂风波再起,安全性成破局关键

20.JAK1抑制剂Itacitinib三期失败:Incyte市值跌20亿美元,信达生物引进中国区权益