scholarly journals Development of a Pharmacodynamic Assay Based on PLCγ2 Phosphorylation for Quantifying Spleen Tyrosine Kinase (SYK)–Bruton’s Tyrosine Kinase (BTK) Signaling

2013 ◽  
Vol 18 (8) ◽  
pp. 890-898 ◽  
Author(s):  
Jonathan Hsu ◽  
Jun Zhang ◽  
Chris Kitson ◽  
Seng-Lai Tan ◽  
Satwant Narula ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Activation ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Activation ◽  
Spleen Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Surface Receptors ◽  
Activation Assay

Spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK) are key mediators in coupling cell surface receptors, such as the B-cell receptor (BCR), to downstream signaling events affecting diverse biological functions. There is therefore tremendous interest in the development of pharmacological inhibitors targeting the SYK-BTK axis for the treatment of inflammatory disorders and hematological malignancies. A good pharmacodynamic (PD) assay, ideally a blood-based assay that measures proximal events, is warranted for evaluation of such inhibitors. In platelets, collagen-induced activation of membrane glycoprotein GPVI is dependent on the SYK-BTK axis. Here, we report the development of a novel immunoassay that uses the dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) to measure GPVI-mediated phosphorylation of phospholipase C γ2 (PLCγ2), a direct substrate of SYK and BTK, in platelets. The assay was validated using SYK or BTK inhibitors and generated IC50 correlated with those from the BCR-induced B-cell activation assay. Furthermore, this assay showed good stability and uniformity over a period of 24 h in different donors. Interestingly, compound IC50 values using blood from patients with rheumatoid arthritis were slightly higher compared with those produced using samples from healthy donors. This novel platelet PLCγ2 phosphorylation-based immunoassay should serve as a promising PD assay for preclinical and clinical development of inhibitors targeting the SYK-BTK axis.

scholarly journals Amplification of IL-21 signalling pathway through Bruton’s tyrosine kinase in human B cell activation

Rheumatology ◽  
2015 ◽  
Vol 54 (8) ◽  
pp. 1488-1497 ◽  
Author(s):  
Sheau-Pey Wang ◽  
Shigeru Iwata ◽  
Shingo Nakayamada ◽  
Hiroaki Niiro ◽  
Siamak Jabbarzadeh-Tabrizi ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Activation ◽  
Signalling Pathway ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Activation ◽  
Bruton's Tyrosine Kinase ◽  
Human B Cell

scholarly journals Targeting Spleen Tyrosine Kinase-Bruton’s Tyrosine Kinase Axis for Immunologically Mediated Glomerulonephritis

2014 ◽  
Vol 2014 ◽  
pp. 1-6
Author(s):  
Jin-Shuen Chen ◽  
Li-Chien Chang ◽  
Shyh-Jer Huang ◽  
Chao-Wen Cheng
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Activation ◽  
Receptor Activation ◽  
Fc Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Spleen Tyrosine Kinase ◽  
Glomerular Injury ◽  
Preclinical Development ◽  
Bruton's Tyrosine Kinase

The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized. The two nonreceptor tyrosine kinases, spleen tyrosine kinase (Syk) and Bruton’s tyrosine kinase (Btk), are primarily expressed by hematopoietic cells, and participate in B-cell-receptor- and Fc-receptor-mediated activation. Pharmacological inhibitors of Syk or Btk are undergoing preclinical development and clinical trials for several immune diseases; and Syk inhibitors have been shown to reduce disease activity in rheumatoid arthritis patients. However, the clinical therapeutic efficacies of these inhibitors in glomerulonephritis have not been evaluated. Herein, we review recent studies of Syk and Btk inhibitors in several experimental primary and secondary glomerulonephritis models. These inhibitors suppressed development of glomerular injury, and also ameliorated established kidney disease. Thus, targeting Syk and Btk signaling pathways is a potential therapeutic strategy for glomerulonephritis, and further evaluation is recommended.

HIV-1 induces B-cell activation and class switch recombination via spleen tyrosine kinase and c-Jun N-terminal kinase pathways

AIDS ◽  
2014 ◽  
Vol 28 (16) ◽  
pp. 2365-2374 ◽  
Author(s):  
Ana Judith Perisé-Barrios ◽  
Rafael Correa-Rocha ◽  
Susana Álvarez ◽  
Maria Ángeles Muñoz-Fernandez ◽  
Marjorie Pion
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Activation ◽  
Class Switch Recombination ◽  
B Cell Activation ◽  
Spleen Tyrosine Kinase ◽  
Class Switch ◽  
Hiv 1

scholarly journals Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease

2020 ◽  
Vol 140 (4) ◽  
pp. 535-548 ◽  
Author(s):  
Sebastian Torke ◽  
Roxanne Pretzsch ◽  
Darius Häusler ◽  
Philipp Haselmayer ◽  
Roland Grenningloh ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Demyelinating Disease ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Functionally Impaired ◽  
Anti Cd20 ◽  
Antigen Presenting

Abstract Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton’s tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties.

scholarly journals Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies

2014 ◽  
Vol 32 (17) ◽  
pp. 1830-1839 ◽  
Author(s):  
Sabine Ponader ◽  
Jan A. Burger
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Btk Inhibitor

Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy.

scholarly journals Novel Indications for Bruton’s Tyrosine Kinase Inhibitors, beyond Hematological Malignancies

2018 ◽  
Vol 7 (4) ◽  
pp. 62 ◽  
Author(s):  
Robert Campbell ◽  
Geoffrey Chong ◽  
Eliza Hawkes
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Hematological Malignancies ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Novel Target

Bruton’s tyrosine kinase (BTK) is a critical terminal enzyme in the B-cell antigen receptor (BCR) pathway. BTK activation has been implicated in the pathogenesis of certain B-cell malignancies. Targeting this pathway has emerged as a novel target in B-cell malignancies, of which ibrutinib is the first-in-class agent. A few other BTK inhibitors (BTKi) are also under development (e.g., acalabrutinib). While the predominant action of BTKi is the blockade of B-cell receptor pathway within malignant B-cells, increasing the knowledge of off-target effects as well as a potential role for B-cells in proliferation of solid malignancies is expanding the indication of BTKi into non-hematological malignancies. In addition to the expansion of the role of BTKi monotherapy, combination therapy strategies utilizing ibrutinib with established regimens and combination with modern immunotherapy compounds are being explored.

Sign in / Sign up

Export Citation Format

Share Document