Chronic urticaria is a heterogeneous, persistent, and severely debilitating disease. Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling. Especially, BTK is critical for the proliferation and survival of leukemic cells in many B cell malignancies. Btk is a cytoplasmic signaling molecule that is crucial for precursor (pre-B) cell differentiation. Btk belongs to the Tec family of cytoplasmic protein tyrosine kinases and plays an essential role in B lymphocyte development and function. In mature B cells, Btk is tyrosine phosphorylated and its kinase activity is increased upon B cell receptor (BCR) stimulation.

Small-molecule inhibitors of BTK have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies currently. In particular, the orally administered BTK inhibitor Remibrutinib associates with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), including patients with high-risk genetic lesions. To date, BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors.

Researchers discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy. The concentration of Remibrutinib required for 50 % inhibition (IC50) is 1 nM against Btk enzymatic activity. Remibrutinib also inhibits Btk enzymatic activity in blood with an IC50 of 23 nM.

Kolkhir P, et al. New treatments for chronic urticaria. Ann Allergy Asthma Immunol. 2019 Aug 23. pii: S1081-1206(19)30603-9.