The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19–infected patients

Treon, Steven P.; Castillo, Jorge J.; Skarbnik, Alan P; Soumerai, Jacob D.; Ghobrial, Irène M.; Guerrera, Maria Luisa; Meid, Kirsten; Yang, Guang

doi:10.1182/blood.2020006288

Cited by 268 publications

(300 citation statements)

References 26 publications

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“…In this line a single cell immune profiling of the temporal dynamics of ibrutinib treatment in CLL patient revealed profound modulation of the non-malignant immune cells and particularly up-regulation of inflammatory pathways in myeloid cells (45). In this context the potential benefits of early phase trials using BTK inhibitors or ruxolitinib in severe COVID-19 patients can be hypothesized to be related to overlapping target specificity and regulation of inflammatory pathways (5,6,46).…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of Bruton's Tyrosine Kinase (BTK) in the treatment of B-cell malignancies has been an exemplary story of functional understanding of disease pathogenesis translating to superior survival rates (1)(2)(3)(4). Moreover, inhibition of BTK is currently also being evaluated as a therapeutic strategy for patients with severe COVID-19 disease (5,6). BTK is localized in proximity of the B-cell receptor (BCR), forming a signalosome complex upon BCR activation with other BCR associated kinases (BAK); LYN, SYK, and PI3K (7,8).…”

Section: Introductionmentioning

confidence: 99%

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Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Barbarino

Henschke

Blakemore

et al. 2020

Preprint

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Targeted inhibition of Bruton's Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenström´s Macroglobulinemia, Mantle cell lymphoma and non-GCB DLBCL. Clinical trials combining small molecule inhibitors with monoclonal antibodies have been initiated at rapid pace, with the biological understanding between their synergistic interactions lagging behind. Here, we have evaluated the synergy between BTK inhibitors and monoclonal antibody therapy via macrophage mediated antibody dependent cellular phagocytosis (ADCP). Initially, we observed increased ADCP with ibrutinib, whilst second generation BTK inhibitors failed to synergistically interact with monoclonal antibody treatment. Kinase activity profiling under BTK inhibition identified significant loss of Janus Kinase 2 (JAK2) only under ibrutinib treatment. We validated this potential off-target effect via JAK inhibition in vitro as well as with CRISPR/Cas9 JAK2 -/experiments in vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage mediated immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Barbarino

Henschke

Blakemore

et al. 2020

Preprint

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“…Ibrutinib has shown anti-tumor effects towards chronic lyphocytic leukemia [20][21][22][23]. It also shown growth inhibitory effect in solid cancers, but the results is limited [24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

The Ibr-7 Derivative of Ibrutinib Exhibits Radiosensitivity in Pancreatic Cancer Cells via Targeting EGFR

Tan¹,

Zhang²,

Yan

et al. 2020

Preprint

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Background: Radiotherapy is one of the main therapeutic methods for pancreatic cancer, but radiation resistance limits the clinical application. As a result, novel therapeutic agents to improve the radiosensitivity is urgent. This study aimed to investigate the effect of Ibr-7 (the derivative of ibrutinib) on radiosensitivity of human pancreatic cancer cells.Methods: The effect of Ibr-7 on pancreatic cancer cell’s proliferation were detected by CCK-8 assay. Radiosensitivity was assessed by clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage was detected by immunofluorescence analysis. The expression of p-EGFR, EGFR were determined by western blot.Results: Ibr-7 showed anti-proliferative effect in PANC-1 and Capan2 cells in a dose- and time-dependent manner. Ibr-7 (2 µmol/L) enhanced the effect of radiation in PANC-1 and Capan2 cells. Further findings showed that this combination enhanced G2/M phase arrest and increased cell apoptosis. Additional molecular mechanism studies revealed that the expression of p-EGFR was decreased by Ibr-7 alone or combined with radiation. Overexpression of EGFR reversed the cell apoptosis induced by Ibr-7 combined with radiation. Moreover, the expression of γ-H2AX was significantly decreased in Ibr-7 combined with radiation group.Conclusions: Our study indicated that the potential application of Ibr-7 as a highly effective radiosensitizer for the treatment of pancreatic cancer cells.

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“…In the clinical treatment of abnormal increases in serum IgM or neoplastic B cells, ibrutinib, which inhibits the activity of Bruton Kinase in the B cell receptor signaling pathway 70 , is now commonly used to reduce the abnormal proliferation of B cells 71,72 . Treon et al reported that the use of ibrutinib may be useful to reduce lung damage from SARS-CoV-2 infection by suppressing the number of B cells 73 . Fingolimod, as an agonist of the S1P1/3 receptor, is thought to inhibit B cell egress out of lymph node through overstimulation of the B cell S1P1/3 receptor 74,75 .…”

Section: Discussionmentioning

confidence: 99%

In silico immune infiltration profiling reveals the role of naïve B cells in lung tissues of COVID-19 patients

Chiu

Wang

et al. 2020

Preprint

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COVID-19 caused by SARS-CoV-2 has rapidly spread to more than 160 countries worldwide since 2020. Despite the tremendous efforts and resources spent around the world trying to explore antiviral drugs, there is still no effective clinical treatment for COVID-19. Approximately 15% of COVID-19 cases progress to pneumonia, patients with severe pneumonia may die from acute respiratory distress syndrome (ARDS). In addition, further pulmonary fibrosis from SARS-CoV-2 infection causes ARDS that often leads to irreversible impairment of lung function. If the mechanisms by which SARS-CoV-2 infection primarily cause immune responses or immune cell infiltration can be identified, it is possible to alleviate or prevent severe lung damage by modulating the infiltration and activation of specific immune cells to mitigate excessive immunity response.The extent to which subsets of immune cells are significantly altered in the lung tissue of COVID-19 patients remains unclear. This study applied the CIBERSORT method to comprehensively evaluate the immune infiltration landscape in lung tissues of COVID-19 patients, and further compared with the one from lung tissue of patients with idiopathic pulmonary fibrosis (IPF). We found several immune cell subtypes; particularly naïve B cells are highly infiltrated in COVID-19 group. A comparison of functional gene set analysis revealed that non-differentiated naïve B cells may be the main cause of the overactive humoral immune response. We further compared several specific COVID-19 cases receiving therapies targeting B cells and found that appropriate suppression of naïve B cells might be a new strategy to alleviate severe symptoms of COVID-19.

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The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19–infected patients

Cited by 268 publications

References 26 publications

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

The Ibr-7 Derivative of Ibrutinib Exhibits Radiosensitivity in Pancreatic Cancer Cells via Targeting EGFR

In silico immune infiltration profiling reveals the role of naïve B cells in lung tissues of COVID-19 patients

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