Department of Medicine, Brigham and Women's Hospital, and Laboratory for Translational Research, Harvard Medical School, Cambridge, Massachusetts 02139, USA.
Cancer Res. 2011 Mar 15;71(6):2298-307. doi: 10.1158/0008-5472.CAN-10-3016. Epub 2011 Jan 20.
Rituximab efficacy in cancer therapy depends in part on induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non-Hodgkin's lymphoma (NHL), and upregulation of hCD59 is an important determinant of the sensitivity of NHL cells to rituximab treatment. Here, we report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo, thereby sensitizing rituximab-resistant lymphoma cells and primary chronic lymphocytic leukemia cells (CLL) to rituximab treatment. By defining pharmcokinetic/pharmacodynamic profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing expression levels of the complement regulators CD59 and CD55 in rituximab-resistant cells occur due to selection of preexisting clones rather than de novo induction of these proteins. Moreover, lymphoma cells overexpressing CD59 were directly responsible for the resistance to rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and CLL. Furthermore, they suggest that preemptive elimination of CD59-overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance.
利妥昔单抗在癌症治疗中的疗效部分取决于补体依赖性细胞毒性（CDC）的诱导。人 CD59（hCD59）是一种关键的补体调节蛋白，可限制膜攻击复合物的形成，从而抑制 CDC 的诱导。hCD59 在 B 细胞非霍奇金淋巴瘤（NHL）中高度表达，hCD59 的上调是 NHL 细胞对利妥昔单抗治疗敏感性的重要决定因素。在这里，我们报告说，强效的 hCD59 抑制剂 rILYd4 增强了体外和体内的 CDC，从而使利妥昔单抗耐药的淋巴瘤细胞和原发性慢性淋巴细胞白血病细胞（CLL）对利妥昔单抗治疗敏感。通过定义 rILYd4 在小鼠中的药代动力学/药效学特征，我们表明 rILYd4 本身不会不利地介导表达 hCD59 的红细胞的体内溶血。利妥昔单抗耐药细胞中补体调节蛋白 CD59 和 CD55 的表达水平增加是由于预先存在的克隆的选择，而不是这些蛋白的从头诱导。此外，过度表达 CD59 的淋巴瘤细胞直接导致对利妥昔单抗介导的 CDC 治疗的耐药性。我们的结果合理地将 rILYd4 用作利妥昔单抗治疗利妥昔单抗耐药性淋巴瘤和 CLL 的治疗佐剂。此外，它们表明在利妥昔单抗治疗的同时预先消除 CD59 过表达亚群可能是消除或克服利妥昔单抗耐药性的有用方法。
