The 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.
The 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.
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DOI：
10.1002/art.41953
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Rao VR
中科院分区：
文献类型：
--
作者：
Winkler A;Sun W;De S;Jiao A;Sharif MN;Symanowicz PT;Athale S;Shin JH;Wang J;Jacobson BA;Ramsey SJ;Dower K;Andreyeva T;Liu H;Hegen M;Homer BL;Brodfuehrer J;Tilley M;Gilbert SA;Danto SI;Beebe JJ;Barnes BJ;Pascual V;Lin LL;Kilty I;Fleming M;Rao VR
研究PF-06650833（一种高效、选择性白细胞介素-1相关激酶4（IRAK 4）小分子抑制剂）在体外、体内和临床环境中自身免疫病理生理学中的作用。通过1）用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）用Toll样受体（TLR）配体刺激RA成纤维细胞样滑膜细胞（FLS）培养物，以及3）暴露于炎症刺激物的其他人原代细胞共培养物，体外模拟风湿性关节炎（RA）炎症病理生理学。在用TLR配体和SLE患者IC刺激的人嗜中性粒细胞、树突状细胞、B细胞和外周血单核细胞中模拟系统性红斑狼疮（SLE）病理生理学。在大鼠胶原诱导的关节炎（CIA）模型和小鼠降植烷诱导的狼疮模型和MRL/lpr模型中对PF-06650833进行了体内评价。最后，使用PF-06650833 I期多次给药剂量递增临床试验中全血样本生成的RNA测序数据检测体内人体药理学。在体外，PF-06650833抑制人原代细胞对RA和SLE患者血浆产生的生理相关刺激的炎症反应。在体内，PF-06650833可降低降植烷诱导和MRL/lpr狼疮小鼠模型中的循环自身抗体水平，并保护大鼠免受CIA的侵害。在一项I期临床试验（NCT 02485769）中，PF-06650833通过降低健康志愿者的全血干扰素基因特征表达，证明了与SLE相关的体内药理作用。这些数据表明，IRAK 4激酶活性的抑制可以降低人类炎症标志物的水平，并为临床开发用于风湿病适应症的IRAK 4抑制剂的基本原理提供了信心。
To investigate the role of PF‐06650833, a highly potent and selective small‐molecule inhibitor of interleukin‐1–associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting. Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti–citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast‐like synoviocyte (FLS) cultures stimulated with Toll‐like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs. PF‐06650833 was evaluated in vivo in the rat collagen‐induced arthritis (CIA) model and the mouse pristane‐induced and MRL/lpr models of lupus. Finally, RNA sequencing data generated with whole blood samples from a phase I multiple‐ascending‐dose clinical trial of PF‐06650833 were used to test in vivo human pharmacology. In vitro, PF‐06650833 inhibited human primary cell inflammatory responses to physiologically relevant stimuli generated with RA and SLE patient plasma. In vivo, PF‐06650833 reduced circulating autoantibody levels in the pristane‐induced and MRL/lpr murine models of lupus and protected against CIA in rats. In a phase I clinical trial (NCT02485769), PF‐06650833 demonstrated in vivo pharmacologic action pertinent to SLE by reducing whole blood interferon gene signature expression in healthy volunteers. These data demonstrate that inhibition of IRAK4 kinase activity can reduce levels of inflammation markers in humans and provide confidence in the rationale for clinical development of IRAK4 inhibitors for rheumatologic indications.
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DOI：
10.1002/art.40504
发表时间：
2018-07
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Falconer J;Murphy AN;Young SP;Clark AR;Tiziani S;Guma M;Buckley CD
通讯作者：
Buckley CD
影响因子：
4.9
作者：
Danto, Spencer, I;Shojaee, Negin;Kilty, Iain
通讯作者：
Kilty, Iain
影响因子：
3.5
作者：
Bouts, Yvette M.;Wolthuis, David F. G. J.;Van der Vlag, Johan
通讯作者：
Van der Vlag, Johan
DOI：
10.1084/jem.20151074
发表时间：
2015-12-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kelly PN;Romero DL;Yang Y;Shaffer AL 3rd;Chaudhary D;Robinson S;Miao W;Rui L;Westlin WF;Kapeller R;Staudt LM
通讯作者：
Staudt LM
影响因子：
4.4
作者：
Douagi, Iyadh;Gujer, Cornelia;Lore, Karin
通讯作者：
Lore, Karin