Characterization of a rituximab variant with potent antitumor activity against rituximab-resistant B-cell lymphoma
Characterization of a rituximab variant with potent antitumor activity against rituximab-resistant B-cell lymphoma
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对利妥昔单抗耐药 B 细胞淋巴瘤具有有效抗肿瘤活性的利妥昔单抗变体的表征
DOI：
10.1182/blood-2009-06-225474
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发表时间：
2009-12-03
期刊：
影响因子：
20.3
通讯作者：
Guo, Yajun
中科院分区：
文献类型：
--
作者：
Li, Bohua;Zhao, Lei;Guo, Yajun
尽管抗cd20单克隆抗体（mAb）利妥昔单抗（rituximab）广泛用于治疗b细胞淋巴瘤，但其疗效仍然不稳定，而且通常是适度的。更好地了解利妥昔单抗介导的杀伤机制对于开发更有效的治疗药物至关重要。在这项研究中，我们通过在其互补性决定区域引入几个点突变来调节利妥昔单抗的结合特性。数据显示，在10(-8)~ 10(-10)M范围内改变利妥昔单抗的结合度可以调节其抗体依赖性细胞毒性，但不影响其补体依赖性细胞毒性和b -淋巴瘤细胞诱导凋亡活性。与之前的发现相反，我们发现CD20单抗的补体依赖性细胞毒性效力与脱除率无关。尽管仍然是I型CD20单抗，但与双突变体（H57DE/H102YK/ H102YK）具有相似结合亲和力的利图昔单抗三突变体（H57DE/H102YK）意外地发现具有极其有效的细胞凋亡诱导活性。此外，这种三重突变体被证明可以有效地启动caspase依赖性和非依赖性细胞凋亡，即使在耐利妥昔单抗淋巴瘤模型中也显示出强大的体内治疗效果，这表明它可能是一种有希望的b细胞淋巴瘤治疗剂。（血液，2009;114:5007-5015）
Despite widespread use of the anti-CD20 monoclonal antibody (mAb), rituximab, in treating B-cell lymphomas, its efficacy remains variable and often modest. A better understanding of rituximab-mediated killing mechanisms is essential to develop more effective therapeutic agents. In this study, we modulated the binding property of rituximab by introducing several point mutations in its complementarity-determining regions. The data showed that changing the binding avidity of rituximab in the range from 10(-8) to 10(-10) M could regulate its antibody-dependent cellular cytotoxicity but not affect its complement-dependent cytotoxicity and apoptosis-inducing activity in B-lymphoma cells. Contradictory to previous findings, we found that the complement-dependent cytotoxicity potency of CD20 mAb was independent of the off-rate. Despite still being a type I CD20 mAb, a rituximab triple mutant (H57DE/H102YK/L93NR), which had a similar binding avidity to a double mutant (H57DE/H102YK), was unexpectedly found to have extremely potent apoptosis-inducing activity. Moreover, this triple mutant, which was demonstrated to efficiently initiate both caspase-dependent and -independent apoptosis, exhibited potent in vivo therapeutic efficacy, even in the rituximab-resistant lymphoma model, suggesting that it might be a promising therapeutic agent for B-cell lymphomas. (Blood. 2009; 114: 5007-5015)