IBRUTINIB Inhibitor of Tyrosine-Protein Kinase BTK Oncolytic

Tyrosine-protein kinase BTK (Bruton tyrosine kinase) is a Tec family cytoplasmic tyrosine kinase that is a key component of the B cell receptor (BCR) signaling pathway and is critical for normal B cell development, differentiation, proliferation and survival. Although BTK is expressed in a number of hematopoietic cells, the absence of BTK predominantly affects B cell function. Individuals without functioning BTK lack circulating B cells and are unable to produce immunoglobulins. BCR signaling pathway genes have been shown to be constitutively increased in B cell malignancies, suggesting that these diseases are likely to be sensitive to therapeutics targeting BTK. Ibrutinib, the first BTK inhibitor to reach widespread clinical development, was designed as a selective and irreversible inhibitor of the BTK protein, and it inhibits signal transduction from the BCR and blocks activation of B cells. Ibrutinib promotes modest direct apoptosis of chronic lymphocytic leukemia (CLL) cells in vitro, but notably, ibrutinib-mediated killing of CLL cells is not abrogated by either stromal cell protection or treatment with protective cytokines produced by the microenvironment. In multiple phase I and Ib/II studies, ibrutinib has been shown to be safe and well tolerated, with most toxicities reported being grade 2 or less, and no cumulative toxicities have been reported to date. In CLL, responses have been seen across all cytogenetic subtypes, with overall response rates previously unseen for a single oral agent. Studies combining ibrutinib with monoclonal antibodies or chemotherapy have demonstrated that these approaches are feasible and effective. In addition to CLL, ibrutinib has shown clinical efficacy across multiple lymphoma histologies, most notably, mantle cell lymphoma, follicular lymphoma and the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma. Registration studies of ibrutinib for relapsed and refractory CLL are under way. Multiple additional BTK inhibitors are in various stages of development, some of which have demonstrated preclinical activity against both B cell neoplasms and autoimmune disorders.