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Cancer Research Is Leading the Way
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Bruton’s tyrosine kinase (BTK) is a crucial enzyme for B-cell differentiation, proliferation, and survival (Pal Singh, Dammeijer, and Hendriks 2018). In the context of B-cell malignancies, including NHL, inhibition of BTK alters cytokine signaling resulting in decreased proliferation and impaired cell migration (Pal Singh, Dammeijer, and Hendriks 2018). The earliest evidence in support of clinical efficacy of BTK inhibitors was generated in a comparative oncology trial in canines with spontaneous lymphoma (Honigberg et al. 2010). This particular trial was unique in that there were no suitable mouse models to utilize for preclinical efficacy evaluation, as mouse models of B-cell lymphoma had impaired B-cell receptor signaling that was dissimilar to humans and canines (Thamm 2019). Thus, the canine lymphoma trial was the first in vivo study to demonstrate proof-of-concept that BTK inhibition could lead to measurable antitumor responses in lymphoma (Honigberg et al. 2010). Additionally, this study was critical for the development of pharmacodynamic assays used in subsequent human clinical trials to ensure adequate drug exposures (Honigberg et al. 2010). The results of this canine oncology trial directly informed human clinical trials, leading to FDA approval for ibrutinib use in several B-cell malignancies (Thamm 2019).
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
X-linked agammaglobulinemia (XLA) results from mutations of the Bruton's tyrosine kinase (BTK) gene. BTK is located on the X chromosome and regulates signaling through the pre-B-cell receptor (pre-BCR) and the BCR. BTK deficiency results in a block at the pro-B to pre-B cell stage in B-cell differentiation in the bone marrow. Accordingly, patients with XLA have a severe reduction or absence of circulating B cells, associated with profound deficiency of all immunoglobulin isotypes. A similar phenotype can also be observed in patients with autosomal recessive forms of agammaglobulinemia, due to mutations of the mu (μ) heavy-chain gene; of the Igα, Igβ, and V pre-B components of the pre-BCR; or of the adaptor molecule B-cell linker protein, which is also involved in pre-BCR-mediated signaling.
Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
This condition is associated with absent B cells and results from a mutation in Bruton's tyrosine kinase (BTK) located on Xq21.2-22. Multiple mutations within these loci lead to the common phenotype of arrested B-cell development in the bone marrow. There are other rare forms of congenital agammaglobulinemia that appear in infancy but are inherited as autosomal recessive traits associated with deletions/mutations in genes encoding parts of either the Vλ region or of the Cμ heavy-chain region.
Cardiotoxicity of BTK inhibitors: ibrutinib and beyond
Published in Expert Review of Hematology, 2022
Bradley W. Christensen, Vlad G Zaha, Farrukh T. Awan
Bruton’s tyrosine kinase (BTK) is a cytoplasmic protein tyrosine kinase that plays a critical role in B-cell development and function [1]. Mutations in the BTK gene located on the X chromosome were initially implicated in the development of X-linked agammaglobulinemia, a primary humoral immunodeficiency characterized by B-cell arrest at the pro-B cell stage and lack of immunoglobulin production [2,3]. Further studies have demonstrated that BTK operates at the crossroads of multiple B-cell signaling pathways (Figure 1). Its most well-described role is as a downstream effector of antigen-dependent B-cell receptor (BCR) signaling. Upon stimulation of the BCR, BTK is phosphorylated by the src-family kinase LYN. In turn, BTK phosphorylates phospholipase C-γ2 (PLC- γ2) and triggers the release of intracellular calcium and the activation of transcription factors involved in B-cell differentiation, proliferation, and survival [4–6]. In addition to its role in the BCR pathway, BTK also mediates CD40, Fc receptors, Toll-like receptors, and chemokine receptor pathway signaling (Figure 1) [7–10]. Given its central contribution to a diverse array of intracellular processes within the B-cell program, it is unsurprising that aberrations in BTK signaling have been implicated in a wide spectrum of autoimmune, immunologic, and malignant conditions in humans [7,11–15].
Emerging treatments for chronic urticaria
Published in Expert Opinion on Investigational Drugs, 2022
Regarding safety, the 1-year ligelizumab extension study demonstrated a similar good safety profile like that of omalizumab. For biologics that are already approved in other indications such as dupilumab, mepolizumab, and benralizumab, new safety signals are not expected from ongoing CU studies. However, the safety profile for CDX-0159 (anti-c-KIT) is still unclear. Preliminary results demonstrated complete depletion of mast cells in the skin 12 weeks after a single infusion [68]. As mast cells are known as pivotal cells in skin and other organ homeostasis and as having a beneficial role in host defense [84–86] their depletion might be harmful. c-KIT is a receptor that is not only involved in mast cell homeostasis but also plays a critical role in melanocyte physiology, survival, proliferation, and migration [87]. Although hair color changes and taste disorders might be reversible [68], patient acceptance of these side effects might be limited. However, it remains to be seen whether these side effects occur also when CDX-0159 is used as subcutaneous formulation. Furthermore, regarding oral selective BTK inhibitors, safety results from phase 3 studies and long-term data are outstanding. Regarding side effects, nonselective and irreversibly binding BTK inhibitors such as ibrutinib increase the risk for infections, atrial fibrillation, bleeding, diarrhea and rash [71]. However, it must be born in mind that these data are derived from patients with B-cell malignancies. Aside from ibrutinib, at present clinical data from long-term clinical trials or real-world data are not available [71].
Update on diagnosis and treatment of immune thrombocytopenia
Published in Expert Review of Clinical Pharmacology, 2021
Rajeev Sandal, Kundan Mishra, Aditya Jandial, Kamal Kant Sahu, Ahmad Daniyal Siddiqui
Most of the adult ITP patients progress to the chronic phase and need lifelong follow-up. Not all patients with ITP need therapy. Only those with platelet count less than 30 × 109/L or bleeding with thrombocytopenia require treatment. The goal of treatment is to achieve a safe platelet count with no bleeding symptoms. Corticosteroid or IVIG/Anti-RhD is usually the first-line therapy that yields a good response. Thrombopoietin receptors agonist (TPO-RAs) and rituximab can be used if first-line drugs fail. Splenectomy is an excellent one-time procedure that yields long-term cure; however, it is less preferred in the modern era and generally reserved for refractory cases. Other medications like danazol, dapsone, cyclosporine, mycophenolate mofetil can be used in patients who fail the previous two lines of therapy. Combination therapy with two or more drugs is also an option for relapsed/refractory cases. New drugs like Bruton’s tyrosine kinase (BTK) inhibitors have shown excellent response in the phase 1/2 trial. Many investigations on new drugs and other treatment modalities are going on in various clinical trials and are expected to bring newer insight into the management of ITP. In our opinion, management should focus more on clinically relevant bleeding episodes than treating low platelet numbers.