Bruton's Tyrosine Kinase (BTK) Inhibitors in Clinical Trials
Bruton's Tyrosine Kinase (BTK) Inhibitors in Clinical Trials
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DOI：
10.1007/s11899-013-0188-8
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发表时间：
2014-03-01
影响因子：
2.9
通讯作者：
Burger, Jan A.
中科院分区：
文献类型：
--
作者：
Burger, Jan A.
BTK是一种细胞质非受体酪氨酸激酶，可传递来自多种细胞表面分子的信号，包括B细胞受体（BCR）和组织归巢受体。遗传BTK缺失导致人类和小鼠的B细胞免疫缺陷，使这种激酶成为B细胞疾病的有吸引力的治疗靶点。BTK抑制剂伊布替尼（PCI-32765，商品名：Imbruvica）在B细胞恶性肿瘤中表现出较高的临床活性，特别是在慢性淋巴细胞白血病（CLL）、套细胞淋巴瘤（MCL）和瓦尔登斯特伦巨球蛋白血症（WM）患者中。因此，伊布替尼被授予这些适应症的“突破性治疗”称号，最近被美国食品和药物管理局批准用于治疗复发性MCL。早期临床开发中的其他BTK抑制剂包括CC-292（AVL-292）和ONO-4059。在CLL和MCL中，伊布替尼的特征性诱导恶性B细胞从组织部位重新分布至外周血中，沿着肿大淋巴结迅速消退和淋巴细胞增多症激增。在持续的伊布替尼治疗中，伊布替尼的生长和存活抑制活性导致大多数患者淋巴细胞计数正常化和缓解。本文综述了BTK抑制剂治疗的临床进展及其病理生理学基础，并概述了BTK抑制剂未来应用的前景。
BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. The BTK inhibitor ibrutinib (PCI-32765, brand name: Imbruvica) demonstrated high clinical activity in B-cell malignancies, especially in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia (WM). Therefore, ibrutinib was granted a 'breakthrough therapy' designation for these indications and was recently approved for the treatment of relapsed MCL by the U.S. Food and Drug Administration. Other BTK inhibitors in earlier clinical development include CC-292 (AVL-292), and ONO-4059. In CLL and MCL, ibrutinib characteristically induces redistribution of malignant B cells from tissue sites into the peripheral blood, along with rapid resolution of enlarged lymph nodes and a surge in lymphocytosis. With continuous ibrutinib therapy, growth- and survival-inhibitory activities of ibrutinib result in the normalization of lymphocyte counts and remissions in a majority of patients. This review discusses the clinical advances with BTK inhibitor therapy, as well as its pathophysiological basis, and outlines perspectives for future use of BTK inhibitors.