Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement-mediated cytolysis.
Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement-mediated cytolysis.
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DOI：
10.1158/0008-5472.can-10-3016
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Qin X
中科院分区：
文献类型：
--
作者：
Hu W;Ge X;You T;Xu T;Zhang J;Wu G;Peng Z;Chorev M;Aktas BH;Halperin JA;Brown JR;Qin X
利妥昔单抗在癌症治疗中的功效部分取决于对补体依赖性细胞毒性（CDC）的诱导。人CD 59（hCD 59）是一种关键的补体调节蛋白，其限制膜攻击复合物的形成，从而抑制CDC的诱导。hCD 59在B细胞非霍奇金淋巴瘤（NHL）中高度表达，并且hCD 59的上调是NHL细胞对利妥昔单抗治疗的敏感性的重要决定因素。在这里，我们报告了有效的hCD 59抑制剂rILYd 4在体外和体内增强CDC，从而使利妥昔单抗耐药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rILYd 4在小鼠中的PK/PD特征，我们表明rILYd 4本身不会不利地介导表达hCD 59的红细胞的体内溶血。补体调节因子CD 59和CD 55在利妥昔单抗耐药细胞中的表达水平增加是由于对预先存在的克隆的选择，而不是这些蛋白质的从头诱导。此外，过度表达CD 59的淋巴瘤细胞直接导致对利妥昔单抗介导的CDC治疗的抗性。我们的研究结果合理使用rILYd 4作为利妥昔单抗治疗利妥昔单抗耐药淋巴瘤和CLL的治疗佐剂。此外，他们认为，与利妥昔单抗治疗一起沿着的CD 59过表达亚群的预先消除可能是消除或克服利妥昔单抗抗性的有用方法。
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 up-regulation 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 PK/PD 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 occurs due to selection of pre-existing 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. Further, they suggest that preemptive elimination of CD59 overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance.