Li Hua-Fei, Wu Cong, Chen Ting, Zhang Ge, Zhao He, Ke Chang-Hong, Xu Zheng
International Joint Cancer Institute, Translation Medicine Institute, the Second Military Medical University, Shanghai, People's Republic of China ; Planning Division, Scientific Research Department, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China ; Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China.
Department of Laboratory Diagnosis, Changhai Hospital, the Second Military Medical University, Shanghai, People's Republic of China.
Int J Nanomedicine. 2015 Jul 30;10:4783-96. doi: 10.2147/IJN.S80129. eCollection 2015.
The CD20-directed monoclonal antibody rituximab (RTX) established a new era in the treatment of non-Hodgkin lymphoma (NHL); however, suboptimal response and/or resistance to RTX still limit its clinical merits. Although four effector mechanisms are validated to participate in CD20-based immunotherapy, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, caspase-dependent apoptosis, and lysosome-mediated programmed cell death (PCD), they could hardly be synchronously activated by any anti-CD20 mAb or mAb derivative until now. Herein, a novel mAb nanocomb (polyethylenimine polymer-RTX-tositumomab [PPRT nanocomb]) was firstly constructed through mass arming two different anti-CD20 mAbs (RTX and tositumomab) to one polymer by nanotechnology. Comparing with free mAbs, PPRT nanocomb possesses a comparable binding ability and reduced "off-rate" to surface CD20 of NHL cells. When treated by PPRT nanocomb, the caspase-dependent apoptosis was remarkably enhanced except for concurrently eliciting complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and lysosome-mediated PCD. Besides, "cross-cell link"-assisted homotypic adhesion by PPRT nanocomb further enhanced the susceptibility to PCD of lymphoma cells. Pharmacokinetic assays revealed that PPRT nanocomb experienced a relatively reduced clearance from peripheral blood compared with free antibodies. With the cooperation of all the abovementioned superiorities, PPRT nanocomb exhibits exceptionally excellent in vivo antitumor activities in both disseminated and localized human NHL xenotransplant models.
靶向CD20的单克隆抗体利妥昔单抗（RTX）开创了非霍奇金淋巴瘤（NHL）治疗的新纪元；然而，对RTX的次优反应和/或耐药性仍然限制了其临床优势。尽管已证实四种效应机制参与基于CD20的免疫治疗，包括补体依赖性细胞毒性、抗体依赖性细胞介导的细胞毒性、半胱天冬酶依赖性凋亡和溶酶体介导的程序性细胞死亡（PCD），但迄今为止，任何抗CD20单克隆抗体或单克隆抗体衍生物都很难同步激活它们。在此，通过纳米技术将两种不同的抗CD20单克隆抗体（RTX和托西莫单抗）大量武装到一种聚合物上，首次构建了一种新型单克隆抗体纳米组合（聚乙烯亚胺聚合物-RTX-托西莫单抗[PPRT纳米组合]）。与游离单克隆抗体相比，PPRT纳米组合对NHL细胞表面CD20具有相当的结合能力和降低的“解离速率”。当用PPRT纳米组合处理时，除了同时引发补体依赖性细胞毒性、抗体依赖性细胞介导的细胞毒性和溶酶体介导的PCD外，半胱天冬酶依赖性凋亡也显著增强。此外，PPRT纳米组合的“跨细胞连接”辅助同型黏附进一步增强了淋巴瘤细胞对PCD的敏感性。药代动力学分析表明，与游离抗体相比，PPRT纳米组合在外周血中的清除率相对降低。凭借上述所有优势的协同作用，PPRT纳米组合在弥漫性和局限性人NHL异种移植模型中均表现出异常出色的体内抗肿瘤活性。
