FcγRⅢa基因多态性影响Rituximab治疗弥漫大B细胞淋巴瘤疗效机制研究

Rituximab is a monoclonal antibody, which binds to the CD20 antigen specifically. It is widely used in B-cell non-Hodgkin's lymphoma, its basic condition is continued coverage more than 80% on the bodyantigen or target. Studies have shown that the half-life of the rituximab display wide individual variability, and its half-life depends on FcR gene polymorphism, which encodes the IgG receptor FcR of patients. By detecting FcγRⅢa gene polymorphism of patients, this subject researches the affinity of the wild-type and mutant-type FcRn cellular localization with rituximab and the dissociation constant KD of rituximab, and screening FcγRⅢa mutation sites. It also detects efficacy and the t1/2 of rituximab in patients'body to define the correlation with FcγRⅢa gene polymorphism. It would attempt to adjust the dose of rituximab base on FcγRⅢa gene type and achieve the purpose of the individual chemotherapy. The implementation of this subject will fill domestic gaps of FcγRⅢa gene research, explore the racial differences, and confirm the correlation of dose of rituximab with FcγRⅢa gene polymorphism. This subject would provides a theoretical and experimental foundation for clinical rational medication and individual chemotherapy of rituximab.

利妥昔单抗(Rituximab)与CD20抗原特异性结合，在B细胞性非霍奇金淋巴瘤治疗中应用广泛，其发挥疗效的最基本条件是持续的覆盖体内80%以上的抗原或靶标。研究显示利妥昔单抗等抗体类药物半衰期个体变异大，其血浆半衰期取决于患者IgG 受体FcR 编码基因的多态性。本课题通过检测肿瘤患者FcγRⅢa 基因多态性，研究野生型和突变型FcR 在细胞定位及其与利妥昔单抗的亲和解离常数KD，筛选具有潜在应用价值的FcγRⅢa突变位点。同时检测利妥昔单抗在患者体内的t1/2 和药效，描绘FcγRⅢa基因多态性与药物药效和t1/2 的关系，并根据FcγRⅢa的类型调整用药而达到个体化给药的目的。本课题的实施将阐明恶性B细胞淋巴瘤患者FcγRⅢa 基因的多态性，确定FcγRⅢa基因多态性与抗体药物代谢的关系，为利妥昔单抗在肿瘤患者临床合理使用提供理论依据。

利妥昔单抗(Rituximab)与 CD20 抗原特异性结合，在 B 细胞性非霍奇金淋巴瘤治疗中应用广泛，其发挥疗效的最基本条件是持续的覆盖体内 80%以上的抗原或靶标。研究显示利妥昔单抗等抗体类药物半衰期个体变异大，其血浆半衰期取决于患者 IgG 受体 FcR 编码基因的多态性。本课题发现FcγRⅢa基因多态性与接受利妥昔单抗治疗的Ⅰ/Ⅱ期弥漫大B细胞淋巴瘤患者的近期疗效和血液学毒性存在相关性，该位点的突变患者（FCGR3A-158V（V/F）基因型）表现出更为优异的近期有效率。利妥昔单抗在FCGR3A基因杂合突变或纯合突变的患者体内的平均血清半衰期要高于其在FCGR3A基因野生型患者体内。较FCGR3A-158F基因型相比，FCGR3A-158V基因型患者的效应细胞膜的FcγRⅢa与利妥昔单抗具有更高的结合力，从而导致该受体所介导的ADCC效应更为有力，并最终提高治疗的有效性。该项目的科学产出发表了2篇SCI论文。本课题的实施阐明了恶性 B 细胞淋巴瘤患者 Fcγ RⅢa 基因的多态性，确定了 Fcγ RⅢa 基因多态性与抗体药物代谢的关系，为利妥昔单抗在肿瘤患者临床合理使用提供理论依据。