Arthritis:白介素1受体相关激酶4抑制剂PF-06650833阻断风湿病临床前模型研究

2022-03-21 医路坦克 MedSci原创

本文探讨了高活性、高选择性的小分子白介素1相关激酶4(IRAK4)抑制剂PF-06650833在自身免疫病理生理中的作用。

     类风湿关节炎(RA)影响约1%的人群,表现为关节疼痛和组织破坏,在血清阳性病例中,其特征是存在抗翻译后修饰蛋白和IgM(类风湿因子)的抗体。参与RA炎症的细胞不仅包括淋巴细胞,还包括中性粒细胞、巨噬细胞、破骨细胞和滑膜成纤维细胞。类风湿性关节炎的治疗方法包括小分子抗风湿药物和生物制剂。随着时间的推移,RA的持续缓解率仍然令人失望地低,这突显了新的治疗机制的必要性。

    系统性红斑狼疮(SLE)也是由自身抗体介导的全身性疾病,其特征在于组织炎症和对包括关节,皮肤和肾脏在内的多器官系统的损伤。已经证明了凋亡和坏死细胞清除的缺陷,允许自身抗体获得核抗原。得到的免疫复合物激活许多免疫细胞类型,包括树突细胞(DC)和B淋巴细胞。SLE的治疗包括糖皮质激素和抗疟药,但疗效有限,长期使用与毒性有关。

    白介素1受体激活的激酶4(IRAK4)是天然免疫反应的中枢调节因子。IRAK4通过结合适配蛋白髓系分化因子88(MyD88),通过IRAK1和IRAK2诱导信号传导,从而传递来自T细胞样受体(TLRs)和白介素1受体(IL-1R)的信号。Myddosome组装的下游结果是激活NF-κB、干扰素调节因子5(IRF-5)和MAPK。在小鼠中,IRAK4的缺失或IRAK4活性的失活可防止多种炎症性疾病模型的炎症发展。来自IRAK4缺陷者的细胞也对通过MyD88(15)发出信号的TLR或IL-1R家族配体没有反应。

   我们最近开发了有效的和选择性的IRAK4抑制剂,但对IRAK1几乎没有活性。在目前的研究中,我们证明了IRAK4的小分子抑制剂PF-06650833在人类细胞以及类风湿性关节炎和系统性红斑狼疮动物模型中降低了对疾病相关刺激的反应。重要的是,我们在I期多剂量递增剂量临床试验中显示,给人类服用PF-06650833导致干扰素基因签名被抑制。我们的发现表明,选择性的IRAK4抑制剂减少了人类的炎症信号,是治疗自身免疫性疾病的潜在疗法。

   目的:探讨高活性、高选择性的小分子白介素1相关激酶4(IRAK4)抑制剂PF-06650833在自身免疫病理生理中的作用。

   体外模拟类风湿关节炎(RA)炎症病理生理的方法有:1)抗瓜氨酸化蛋白抗体免疫复合物(IC)刺激原代人巨噬细胞;2)Toll样受体(TLR)配体刺激RA成纤维样滑膜细胞(FLS)培养;3)体外培养暴露于炎症刺激的原代细胞。模拟系统性红斑狼疮(SLE)患者的中性粒细胞、树突状细胞、B细胞和外周血单个核细胞在TLR配体和SLE患者IC刺激下的病理生理学变化。在大鼠胶原诱导性关节炎(CIA)模型和小鼠Pristane诱导的狼疮模型和MRL/LPR模型中,对PF-06650833进行了体内评价。最后,使用PF-06650833 I期多剂量递增剂量临床试验的全血样本产生的RNA测序数据用于体内人类药理学测试。

   在体外,PF-06650833抑制人类原代细胞对类风湿性关节炎和系统性红斑狼疮患者血浆产生的生理相关刺激的炎症反应。在体内,PF-06650833降低了Pristane诱导的和MRL/lpr狼疮小鼠模型中的循环自身抗体水平,并在大鼠中保护了对CIA的保护作用。在I期临床试验(NCT02485769)中,PF-06650833通过减少健康志愿者的全血干扰素基因签名表达,展示了与系统性红斑狼疮相关的体内药理作用。

   这些数据表明,抑制IRAK4激酶活性可以降低人类炎症标志物的水平,并为临床开发IRAK4抑制剂用于风湿病适应症的理论提供了信心。

文献来源:Aaron Winkler,Weiyong Sun,Saurav DeThe ,Interleukin- 1 Receptor– Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial,Arthritis & Rheumatology.Vol. 73, No. 12, December 2021, pp 2206–2218

 

 

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    2022-09-02 jklm09
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    2022-03-23 zhaojie88
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  6. [GetPortalCommentsPageByObjectIdResponse(id=1972791, encodeId=2a7419e279194, content=<a href='/topic/show?id=8a6a2e8839' target=_blank style='color:#2F92EE;'>#Arthritis#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2788, encryptionId=8a6a2e8839, topicName=Arthritis)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIibticIBly5jCSic5ZElW4He3rO4DMpUHUFaFX57OicNMnzckWaicBNeStwugWHFCuOdicoakApM4HGmtw/132, createdBy=f8672500006, createdName=ms6390871039024434, createdTime=Tue Jul 26 21:56:49 CST 2022, time=2022-07-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1710305, encodeId=c5ea1e10305c5, content=<a href='/topic/show?id=7ac59e67604' target=_blank style='color:#2F92EE;'>#阻断#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97676, encryptionId=7ac59e67604, topicName=阻断)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b5ca31824852, createdName=41514497@qq.com, createdTime=Wed May 18 09:56:49 CST 2022, time=2022-05-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1852916, encodeId=e5d7185291607, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Fri Sep 02 08:56:49 CST 2022, time=2022-09-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1357894, encodeId=ec15135e89432, content=<a href='/topic/show?id=b0702e84b9' target=_blank style='color:#2F92EE;'>#ART#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2784, encryptionId=b0702e84b9, topicName=ART)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=zhaojie88, createdTime=Wed Mar 23 03:56:49 CST 2022, time=2022-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1372154, encodeId=b7a613e215423, content=<a href='/topic/show?id=6ca1e1621c4' target=_blank style='color:#2F92EE;'>#白介素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71621, encryptionId=6ca1e1621c4, topicName=白介素)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0e95336, createdName=budeshao, createdTime=Wed Mar 23 03:56:49 CST 2022, time=2022-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1496116, encodeId=a5a3149611688, content=<a href='/topic/show?id=9c516685eea' target=_blank style='color:#2F92EE;'>#激酶#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=66857, encryptionId=9c516685eea, topicName=激酶)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=73449239400, createdName=redcrab, createdTime=Wed Mar 23 03:56:49 CST 2022, time=2022-03-23, status=1, ipAttribution=)]
    2022-03-23 redcrab

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