Dybowski Sarah, Torke Sebastian, Weber Martin S
Institute of Neuropathology, University Medical Center, Göttingen, Germany.
Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
JAMA Neurol. 2023 Apr 1;80(4):404-414. doi: 10.1001/jamaneurol.2022.5332.
Currently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing immune cell proliferation, inhibiting immune cell migration, or cellular depletion. Over the last decades, the repertoire substantially increased because of the conceptual progress that not only T cells but also B cells play an important pathogenic role in MS, fostered by the empirical success of B cell-depleting antibodies against the surface molecule CD20. Notwithstanding this advance, a continuous absence of B cells may harbor safety risks, such as a decline in the endogenous production of immunoglobulins. Accordingly, novel B cell-directed MS therapies are in development, such as inhibitors targeting Bruton tyrosine kinase (BTK).
BTK is centrally involved in the B cell receptor-mediated activation of B cells, one key requirement in the development of autoreactive B cells, but also in the activation of myeloid cells, such as macrophages and microglia. Various compounds in development differ in their binding mode, selectivity and specificity, relative inhibitory concentration, and potential to enter the central nervous system. The latter may be important in assessing whether BTK inhibition is a promising strategy to control inflammatory circuits within the brain, the key process that is assumed to drive MS progression. Accordingly, clinical trials using BTK inhibitors are currently conducted in patients with relapsing-remitting MS as well as progressive MS, so far generating encouraging data regarding efficacy and safety.
While the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors in the treatment of inflammatory CNS disease. Potential changes in circulating antibody levels should be evaluated and compared with B cell depletion. Also important is the potential of BTK inhibitors to enter the CNS, which depends on the given compound. Remaining questions involve where BTK inhibitors fit in the landscape of MS therapeutics. A comparative analysis of their distinct properties is necessary to identify which inhibitors may be used in relapsing vs progressive forms of MS as well as to clarify which agent may be most suitable for sequential use after anti-CD20 treatment.
目前，用于治疗多发性硬化症（MS）的疾病修正疗法有4种作用机制：免疫调节、抑制免疫细胞增殖、抑制免疫细胞迁移或细胞耗竭。在过去几十年中，由于概念上的进展，即不仅T细胞而且B细胞在MS中发挥重要的致病作用，这一疗法种类大幅增加，这一进展得益于针对表面分子CD20的B细胞耗竭抗体在实践中的成功。尽管有这一进展，但持续缺乏B细胞可能存在安全风险，如内源性免疫球蛋白产生下降。因此，新型的针对B细胞的MS疗法正在研发中，如靶向布鲁顿酪氨酸激酶（BTK）的抑制剂。
BTK在B细胞受体介导的B细胞激活中起核心作用，这是自身反应性B细胞发育的一个关键要求，同时也参与髓样细胞（如巨噬细胞和小胶质细胞）的激活。正在研发的各种化合物在结合模式、选择性和特异性、相对抑制浓度以及进入中枢神经系统的潜力方面存在差异。后者对于评估BTK抑制是否是控制大脑内炎症回路（这一被认为驱动MS进展的关键过程）的有前景的策略可能很重要。因此，目前正在复发缓解型MS以及进展型MS患者中开展使用BTK抑制剂的临床试验，到目前为止已产生了关于疗效和安全性的令人鼓舞的数据。
虽然靶向BTK的新方法很有前景，但仍有几个问题未得到解答，例如在炎症性中枢神经系统疾病治疗中使用BTK抑制剂的长期影响。应评估循环抗体水平的潜在变化，并与B细胞耗竭情况进行比较。同样重要的是BTK抑制剂进入中枢神经系统的潜力，这取决于特定的化合物。其余问题包括BTK抑制剂在MS治疗格局中的位置。有必要对它们的不同特性进行比较分析，以确定哪些抑制剂可用于复发型与进展型MS，以及阐明哪种药物可能最适合在抗CD20治疗后序贯使用。
