口服布鲁顿酪氨酸激酶抑制剂——依鲁替尼

依鲁替尼(ibrutinib,商品名Imbruvica)是由Pharmacyclics公司和强生旗下子公司杨森制药共同研制的第一个口服布鲁顿酪氨酸激酶抑制剂。至2015年1月,FDA已批准其用于4种B细胞恶性肿瘤的治疗,在其他B细胞淋巴瘤适应证的扩展研究仍值得期待。依鲁替尼通过对布鲁顿酪氨酸激酶的不可逆抑制机制发挥疗效,其被认为是迄今为止治疗套细胞淋巴瘤最重要的突破,并有望把慢性淋巴细胞白血病从死刑判决变成可控制的慢性疾病。笔者就依鲁替尼的研发历程、基本性质、作用机制、药动学、药效学、临床试验及应用等研发动态作一概述,以期能为医院临床用药起到指导作用。     

泽布替尼在B细胞恶性肿瘤治疗中的研究进展

泽布替尼是我国自主研发的一款口服布鲁顿酪氨酸激酶(BTK)选择性小分子抑制剂,通过与BTK结合抑制BTK磷酸化,从而阻断B细胞受体(BCR)信号通路和下游多条信号通路,发挥抗肿瘤作用。在慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)、套细胞淋巴瘤(MCL)及华氏巨球蛋白血症(WM)等获批适应证中显示出良好疗效,且耐受性较传统化疗或化学免疫方案更优。在其他类型的B细胞恶性肿瘤中,泽布替尼也逐步走进临床视野。本文结合近年来最新的临床数据,概述泽布替尼在B细胞恶性肿瘤治疗中的研究进展。     

依鲁替尼：一种新型布鲁顿酪氨酸激酶抑制剂

依鲁替尼是布鲁顿酪氨酸激酶（BTK）抑制剂,用于治疗慢性淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）。MCL和CLL均属于B细胞非霍奇金淋巴瘤,具有难治愈性和易复发性,常用的化学免疫疗法不具备靶向性,常发生3或4级不良反应。依鲁替尼可与B淋巴细胞形成、分化、信息传递和生存所必需的BTK靶向性结合,不可逆地抑制BTK的活性,有效抑制肿瘤细胞的增殖和存活;且口服后吸收迅速,1~2 h达最大血药浓度,不良反应属于1或2级,将成为治疗CLL和MCL的新选择。     

Bruton酪氨酸激酶抑制剂伊鲁替尼治疗B细胞恶性肿瘤的临床应用

Bruton酪氨酸激酶(bruton tyrosine kinase,BTK)是B细胞内一种非受体型酪氨酸激酶,介导了B细胞抗原受体(BCR)在内的一系列细胞通路,其异常活性与B细胞恶性肿瘤的发病密切相关。伊鲁替尼(ibrutinib)是一种高效选择性BTK抑制剂,能够在钠摩尔水平下抑制肿瘤细胞增殖。本文介绍了伊鲁替尼的药理学特点,并且综述了其治疗慢性淋巴细胞白血病、套细胞淋巴瘤等疾病的临床应用。     

依鲁替尼衍生物的研究进展

摘 要依鲁替尼（ibrutinib）作为第一代布鲁顿酪氨酸激酶（BTK）抑制药,具有高度的专一性、起效迅速、不良反应小等优点。以其为先导结构进行结构改造,深入研究开发具有更高效的抗肿瘤药物,已取得非常丰富的研究成果。本文对近年来对依鲁替尼结构修饰工作进行简要归纳综述。     

治疗B细胞淋巴瘤新药:泽布替尼

泽布替尼是由中国百济神州公司开发的新型选择性布鲁顿酪氨酸激酶(BTK)抑制剂,2019年11月被美国食品和药物管理局批准用于治疗既往至少接受过一种治疗的成人套细胞淋巴瘤(MCL)患者.2020年6月初,我国药品监督管理局批准其用于治疗既往至少接受过一种治疗的成人MCL和慢性淋巴细胞白血病/小淋巴细胞性淋巴瘤(CLL/S...     

弥漫性大B细胞淋巴瘤常见致病信号通路及其靶向药物的研究进展

弥漫性大B细胞淋巴瘤是亚洲人最常见的淋巴肿瘤亚型,经过R-CHOP方案治疗后仍有相当一部分患者表现为难治或复发。弥漫性大B细胞淋巴瘤的常见致病信号通路有B细胞受体、Toll样受体4/髓样分子因子88/核因子-κB、磷脂酰肌醇3-激酶/蛋白激酶B信号通路,靶向药物包括Bruton酪氨酸激酶抑制剂、来那度胺、硼替佐米、凋亡蛋白抑制剂抑制剂、磷脂酰肌醇3-激酶抑制剂、蛋白激酶B抑制剂、哺乳动物雷帕霉素靶蛋白抑制剂。阐述了弥漫性大B细胞淋巴瘤中常见致病信号通路及其遗传学改变,并总结了相关通路常见的靶向药物的研究进展。     

Bcr-Abl酪氨酸激酶抑制剂联合用药治疗慢性粒细胞白血病研究进展

以伊马替尼为代表的酪氨酸激酶抑制剂对慢性粒细胞白血病(CML)的治疗产生了重要影响,但其耐药性已成为CML治疗领域的关键问题。伊马替尼、尼洛替尼、达沙替尼以及普纳替尼等Bcr-Abl酪氨酸激酶抑制剂与其他药物联合使用,可以协同抑制Bcr-Abl及其磷酸化蛋白的表达,显著降低STAT5、CRKL、ERK5等信号通路的磷酸化水平,改善肿瘤微环境,降低肿瘤细胞多药耐药性,已在基础研究和临床Ⅰ期研究中取得阶段性成果,为治疗CML提供新策略。     

非小细胞肺癌患者的新选择—盐酸埃克替尼

盐酸埃克替尼是第一个国产靶向治疗非小细胞肺癌,口服的小分子酪氨酸激酶抑制剂。与吉非替尼和厄洛替尼具有相似的作用机制,其特点是在不同水平特异性、竞争性地结合在EGFR激酶功能区,抑制其激酶活性从而阻断癌细胞增殖、转移等相关信号的传导。临床用于治疗既往接受过1种或2种化疗的局部晚期或转移的非小细胞肺癌。本文对化学结构和作用机制、基础药理学和药效学、临床前研究、临床研究、耐受性和安全性、上市后至现阶段专家共识等方面对其做一综述。     

Janus激酶靶点药物国内外研发总览

Janus激酶（JAK）是一类非受体型酪氨酸蛋白激酶家族,包括JAK1,JAK2,TYK2和JAK3。JAK/STAT信号通路对调控免疫系统、促进细胞生长、抗凋亡及促进细胞周期等发挥重要作用,作用于JAK靶点的药物已广泛用于血液系统疾病、肿瘤、类风湿性关节炎和银屑病等治疗,并且不断扩展新的适应证。目前,全球JAK靶点药物研发及临床研究取得新进展,并取得巨大的市场成功。全球共批准上市JAK靶点药物10个,申请上市1个,临床Ⅲ期8个,临床Ⅱ期20个,临床Ⅰ期23个。在国内已经上市的有5个：磷酸芦可替尼、枸橼酸托法替布、巴瑞替尼、乌帕替尼和阿布昔替尼,氢溴酸吡西替尼、氘可来昔替尼（BMS-986165）和硫酸伊伐马替尼（SHR-0302）也完成了部分适应证的临床研究。但同时JAK靶点药物的安全问题也逐步显现,今后亟待加强对此类药物不良反应的监测工作。     

Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

Introduction: Ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK), is approved in many countries for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) and for previously untreated disease with a 17p deletion and, most recently, as a frontline therapy for CLL. In controlled trials in CLL, ibrutinib produced high response rates and improved survival in both the frontline and relapsed settings. While ibrutinib controls CLL with impressive efficacy, it only infrequently induces complete remissions, particularly of relapsed CLL, and does not eradicate minimal residual disease. Finally, ibrutinib is extremely expensive, has off-target toxicities, and requires indefinite therapy.

Areas covered: In this article, we provide an overview of the CLL therapeutic landscape and discuss the pharmacokinetic and pharmacodynamic aspects of ibrutinib. Major clinical trials of ibrutinib in CLL are summarized, and its safety profile explored.

Expert opinion: Ibrutinib represents a transformative advance in CLL management and has validated BTK as a therapeutic target in this disease, but has some limitations, leading to the emergence of other BTK inhibitors and mechanism-based combination strategies. Given complete BTK occupancy at lower doses of ibrutinib and declining levels of BTK on ibrutinib therapy, lower doses of ibrutinib in CLL are being explored.     

复方金钱草颗粒的质量控制研究

目的建立复方金钱草颗粒的质量控制方法,为其质量控制提供依据。方法采用薄层色谱法对复方金钱草颗粒处方中广金钱草、光石韦药材进行定性鉴别,采用高效液相色谱法测定复方金钱草颗粒中芒果苷。结果确定了处方中广金钱草、光石韦的薄层色谱鉴别方法,在选定的薄层色谱条件下,色谱斑点分离较好,阴性无干扰。芒果苷进样量在0.060 5~0.605 0μg与峰面积呈良好的线性关系(r=0.999 5),平均回收率为99.52%,RSD值为2.13%。结论所建立的方法简便、准确、专属性强、重复性好,可有效地控制复方金钱草颗粒的质量。     

Anovel BTK inhibitor SIMM-016, ameliorates rheumatoid arthritis by dual inhibition of BCR and osteoclastogenic signaling

OBJECTIVE To investigate the potential effect and mechanism of BTK inhibitor SIMM-016 on RA.METHODS The mouse model of collagen-induced arthritis(CIA) was used to evaluate the therapeutic effects of SIMM-016. Activated markers of splenic B cells from mice treated with BTK inhibitors upon anti-IgM or typeⅡcollagen(CⅡ) stimulation were examined by flow cytometry. To define direct effects of BTK inhibitors on osteoclastogenesis, osteoclasts(OCs) were enumerated by tartrate-resistant acid phosphatase(TRAP) staining,RANK-BTK signaling was assessed by Western blotting.PBMC of RA patients and healthy controls was stimulated with anti-IgM and anti-CD40 to evaluate whether BTK inhibition affected RANKL expression of memory B cells.RESULTS In vitro, SIMM-016 has far superior selectivity to Ibrutinib and better activity than A calabrutinib(ACP-196) on BTK inhibition in B cell. In vivo, SIMM-016 dosedependently reduced serum CⅡ specific antibodies and ameliorated bone destruction in CIA mice, exhibited more potent efficacy than Ibrutinib and ACP-196. Moreover, SIMM-016 treatment decreased expression of inflammatory cytokines and osteoclastogenic genes in joints of CIA mice. SIMM-016 inhibited osteoclast differentiation and abolished transduction of RANK-BTK-PLCγ2-NFATc1 signaling in RANKL/M-CSF stimulated RAW264.7 cell. Notably, SIMM-016 reduced RANKL expression of memory B cells in PBMC of RA patients. CONCLUSION SIMM-016 is a highly potent and selective BTK inhibitor,which presents distinguished therapeutic effects in the CIA model. Our results demonstrated a dual inhibition of B cell function and osteogenesis by SIMM-016, and characterized it as a promising drug candidate for RA treatment.     

Bruton’s tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL)

Introduction: The BTK inhibitor ibrutinib is effective in both low- and high-risk CLL patients, achieving durable remissions with continuous therapy in the majority of patients. Ibrutinib lacks myelotoxicity and is generally well tolerated by older and unfit patients; however, side effects, such as atrial fibrillation or hemorrhage, can result in treatment interruption or discontinuation. Given the high efficacy and overall safety, ibrutinib is increasingly used in untreated and previously treated CLL patients. Second-generation BTK inhibitors are being developed, with different and generally more BTK-selective kinase inhibition profiles, which may increase the safety and/or efficacy.

Areas covered: We review key features of ibrutinib, along with problems of its use, discuss the potential and drawbacks of second generation molecules, and discuss combination therapies currently in development.

Expert Opinion: BTK inhibitors have been a major therapeutic advance in older/unfit patients and those with high-risk and/or relapsed CLL, but require indefinite maintenance therapy and risk of developing treatment resistance or adverse events requiring treatment cessation increases over time. Novel combination strategies are currently being evaluated (e.g. the combination of ibrutinib with venetoclax), which may achieve greater depth of remission, remove the need for indefinite maintenance treatment and potentially replace chemoimmunotherapy in the first-line setting.     

MYD88 L265P基因突变在华氏巨球蛋白血症中的意义研究进展

MYD88 L265P基因突变是指染色体3p22.2上的单个核苷酸的改变,该突变可以导致NF-κB信号传导通路的异常活化,从而促进细胞恶性增殖.全基因组测序技术已经证实该突变广泛存在于华氏巨球蛋白血症(WM)中,对WM的诊断、鉴别诊断、预后判断及治疗方面均有重要意义.酪氨酸激酶(BTK)抑制剂依鲁替尼的出现为WM的靶向治疗提供了选择.     

Ibrutinib-A double-edge sword in cancer and autoimmune disorders

Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton’s tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.     

Bruton’s tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018)

Introduction: Bruton’s tyrosine kinase (BTK) plays a critical role in the regulation of survival, proliferation, activation and differentiation of B-lineage cells. It participates by regulating multiple cellular signaling pathways, including B cell receptor and FcR signaling cascades. BTK is abundantly expressed and constitutively active in the pathogenesis of B cell hematological malignancies, as well as several autoimmune diseases. Therefore, BTK is considered as an attractive target for treatment of B-lineage lymphomas, leukemias, and some autoimmune diseases. Many industry and academia efforts have been made to explore small molecular BTK inhibitors.

Areas covered: This review aims to provide an overview of the patented BTK inhibitors for the treatment of cancer from 2010 to 2018.

Expert opinion: BTK inhibitors attract much interest for their therapeutic potential in the treatment of cancers and autoimmune diseases, especially for B cell hematological malignancies. In 2013, ibrutinib was approved by the FDA as the first-in-class BTK inhibitors for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), and now it is also undergoing clinical evaluation for other indications in either single or combined therapy. It is clear that BTK inhibitors can provide a promising clinical benefit in treating B-lineage lymphomas and leukemias.     

伊布替尼致不良反应文献分析

目的：分析伊布替尼所致不良反应（ADRs）的发生情况及临床特点，为临床安全用药提供参考。方法：检索PubMed、Web of Science、中国知网数据库、维普中文科技期刊数据库、万方数据库、中国医院知识总库关于伊布替尼不良反应的文献并进行分析。结果：伊布替尼致ADRs的个案共41例，多发生在用药30d内（13例，31.7%）；伊布替尼致ADRs累及系统-器官以呼吸系统损害（13例，28.9%）、皮肤及附件损害为主（10例，22.2%）为主。结论：临床医师或药师应了解伊布替尼ADRs的发生规律和特点，尽量将ADRs的影响及危害降至最低，最大程度保障用药安全。