Cancer Research Center of Toulouse, CHU Purpan, Place du Dr Baylac, Toulouse, 31024 France.
Mol Cancer Res. 2011 Nov;9(11):1435-42. doi: 10.1158/1541-7786.MCR-11-0154. Epub 2011 Sep 15.
The anti-CD20 monoclonal antibody rituximab is the backbone of treatment for the B-cell malignancies non-Hodgkin lymphoma and chronic lymphocytic leukemia. However, there is a wide variability in response to rituximab treatment, and some patients are refractory to current standard therapies. Rituximab kills B cells by multiple mechanisms of action, including complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which are immune-mediated mechanisms, as well as by direct effects on cell signaling pathways and cell membranes following CD20 binding. A large number of events that are affected by rituximab binding have been identified, including lipid raft modifications, kinase and caspase activation, and effects on transcription factors and apoptotic/antiapoptotic molecules. Studies on cell lines and isolated tumor cells have shown that by targeting these pathways, it may be possible to increase or decrease susceptibility to rituximab cell killing. An increased understanding of the direct effects of rituximab may therefore aid in the design of new, rational combinations to improve the outcome of CD20-based therapy for patients who currently have suboptimal outcome following standard treatments.
抗 CD20 单克隆抗体利妥昔单抗是治疗 B 细胞恶性肿瘤非霍奇金淋巴瘤和慢性淋巴细胞白血病的基础。然而，对利妥昔单抗治疗的反应存在很大的变异性，有些患者对目前的标准治疗方法有抗药性。利妥昔单抗通过多种作用机制杀死 B 细胞，包括补体依赖性细胞毒性和抗体依赖性细胞毒性，这些都是免疫介导的机制，以及通过与 CD20 结合后直接影响细胞信号通路和细胞膜。已经确定了大量受利妥昔单抗结合影响的事件，包括脂筏修饰、激酶和半胱天冬酶的激活，以及对转录因子和凋亡/抗凋亡分子的影响。对细胞系和分离的肿瘤细胞的研究表明，通过靶向这些途径，可能增加或降低对利妥昔单抗细胞杀伤的敏感性。因此，对利妥昔单抗直接作用的深入了解可能有助于设计新的、合理的组合，以改善目前标准治疗后疗效不佳的 CD20 为基础的治疗患者的预后。
