Inhibition of Bruton tyrosine kinase in patients with severe COVID-19

Autor: M. Andrew Monticelli, Raquel Izumi, Jeff P. Sharman, Joseph Roswarski, Jacob F. Collen, Jigar V. Desai, Louis M. Staudt, Michail S. Lionakis, Marissa A. Zarakas, Andre Goy, Michael Roshon, Ahmed Hamdy, Stephen H. Wrzesinski, José Baselga, George E. Wright, Keith M. Rose, Mark Roschewski, Wyndham H. Wilson, Kevin K. Chung
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
medicine.medical_treatment
Gastroenterology
Monocytes
0302 clinical medicine
immune system diseases
hemic and lymphatic diseases
Agammaglobulinaemia Tyrosine Kinase
Prospective Studies
Prospective cohort study
Research Articles
Aged
80 and over
biology
General Medicine
Middle Aged
Treatment Outcome
Pyrazines
030220 oncology & carcinogenesis
Benzamides
Toxicity
Acalabrutinib
Female
medicine.symptom
Coronavirus Infections
medicine.medical_specialty
Critical Illness
Pneumonia
Viral
Immunology
Inflammation
Betacoronavirus
03 medical and health sciences
Internal medicine
medicine
Humans
Bruton's tyrosine kinase
Pandemics
Aged
Mechanical ventilation
Interleukin-6
SARS-CoV-2
business.industry
R-Articles
COVID-19
Oxygenation
Respiration
Artificial
COVID-19 Drug Treatment
Coronavirus
030104 developmental biology
biology.protein
business
Ex vivo
Follow-Up Studies
Zdroj: Science Immunology
ISSN: 2470-9468
DOI: 10.1126/sciimmunol.abd0110
Popis: Acalabrutinib targets activated BTK in macrophages and was associated with reduced inflammation and clinical improvement in COVID-19.
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.
Databáze: OpenAIRE
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