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Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.
Science Immunology ( IF 17.6 ) Pub Date : 2020-06-05 , DOI: 10.1126/sciimmunol.abd0110
Mark Roschewski 1 , Michail S Lionakis 1 , Jeff P Sharman 1 , Joseph Roswarski 1 , Andre Goy 1 , M Andrew Monticelli 1 , Michael Roshon 1 , Stephen H Wrzesinski 1 , Jigar V Desai 1 , Marissa A Zarakas 1 , Jacob Collen 1 , Keith Rose 1 , Ahmed Hamdy 1 , Raquel Izumi 1 , George W Wright 1 , Kevin K Chung 1 , Jose Baselga 1 , Louis M Staudt 1 , Wyndham H Wilson 2
Affiliation  

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation – C-reactive protein and IL-6 – normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.



中文翻译:


严重 COVID-19 患者中布鲁顿酪氨酸激酶的抑制。



重症 COVID-19 患者存在高炎症免疫反应,提示巨噬细胞激活。布鲁顿酪氨酸激酶 (BTK) 调节巨噬细胞信号传导和激活。 Acalabrutinib 是一种选择性 BTK 抑制剂,对 19 名因重症 COVID-19 住院的患者(11 名接受补充供氧;8 名接受机械通气)进行超说明书给药,其中 18 名患者在基线时氧气需求增加。在 10-14 天的治疗过程中,acalabrutinib 通常在 1-3 天内改善了大多数患者的氧合,并且没有明显的毒性。大多数患者的炎症指标(C 反应蛋白和 IL-6)很快恢复正常,淋巴细胞减少症也是如此,这与氧合改善相关。在 acalabrutinib 治疗结束时,吸氧组中 8/11 (72.7%) 的患者已出院,呼吸室内空气,机械通气组中 4/8 (50%) 的患者已成功拔管,其中 2/8 (25%) 排放到室内空气中。离体分析显示,与健康志愿者的血液单核细胞相比,自磷酸化证明了 BTK 活性显着升高,并且重症 COVID-19 患者的血液单核细胞中 IL-6 的产生增加。这些结果表明,用 BTK 抑制剂针对过度的宿主炎症是严重 COVID-19 的一种治疗策略,并已引发一项验证性国际前瞻性随机对照临床试验。

更新日期:2020-06-05
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