抗CD20治疗性抗体Rituximab的耐药机制研究

抗CD20抗体Rituximab于1997年获批用于B细胞非霍奇金淋巴瘤的治疗。尽管Rituximab显示出良好疗效，但约60％对Rituximab首次治疗产生反应的患者对Rituximab再次治疗产生耐药。阐明Rituximab耐药机制、克服其耐药是临床上的迫切需求。在前期研究中，我们通过模拟患者对Rituximab产生耐药的过程建立了Rituximab耐药B淋巴瘤细胞株，并且通过计算机辅助设计获得了一株能有效杀伤Rituximab耐药B细胞淋巴瘤的CD20抗体Rituximabmut。在本项目中，我们将建立多对Rituximab敏感和耐药B淋巴瘤细胞株，利用前期获得的Rituximabmut，同时借助基因芯片和蛋白质组学技术寻找候选耐药相关分子并进行功能鉴定，阐明Rituximab耐药机制。这个项目的开展将为发展更为有效的Rituximab耐药B细胞淋巴瘤的治疗策略提供基础。

The anti-CD20 chimeric antibody rituximab was approved for treatment of B-cell non-Hodgkin's lymphomas in 1997. Despite its effectiveness, approximately 60% of prior rituximab responding patients will not longer benefit with re-treatment with this monoclonal antibody. Elucidating the molecular mechanisms underlying rituximab resistance and overcoming rituximab resistance represents an important challenge to improving outcomes for patients with B-cell non-Hodgkin's lymphomas. In our previous studies, we established rituximab-resistant B-lymphoma cell lines by modelling the development of acquired resistance in patients. Moreover, we obtained a rituximab mutant (rituximabmut) by a computational design method, and rituximabmut exhibited potent therapeutic efficacy in the rituximab-resistant lymphoma model. In the present study, we will eastablished several pairs of rituximab-sensitive and -resistant lymphoma cell lines. The antitumor mechanisms of action of rituximabmut will be also disclosed. With the help of gene chip and proteomics technology, we will elucidate the molecular mechanisms of resistance to rituximab. The results of this study will help to develop more effective therapeutic strategies for treatment of rituximab-resistant B-cell lymphomas.