rILYd4, a Human CD59 Inhibitor, Enhances Complement-Dependent Cytotoxicity of Ofatumumab against Rituximab-Resistant B-cell Lymphoma Cells and Chronic Lymphocytic Leukemia
rILYd4, a Human CD59 Inhibitor, Enhances Complement-Dependent Cytotoxicity of Ofatumumab against Rituximab-Resistant B-cell Lymphoma Cells and Chronic Lymphocytic Leukemia
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DOI：
10.1158/1078-0432.ccr-11-0647
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发表时间：
2011-11-01
影响因子：
11.5
通讯作者：
Qin, Xuebin
中科院分区：
文献类型：
--
作者：
Ge, Xiaowen;Wu, Lin;Qin, Xuebin
目的：ofatumab是一种新近被批准用于治疗氟达拉滨和阿伦图珠单抗难治性慢性淋巴细胞白血病(CLL)的抗CD20抗体，其介导的补体依赖性细胞毒(CDC)比利妥昔单抗强得多。人CD59是抑制CDC的关键膜补体调节因子，在B细胞肿瘤中高表达，其上调是B细胞肿瘤对利妥昔单抗治疗敏感性的重要决定因素。此前，我们已经证明了有效的CD59抑制剂rILYd4使利妥昔单抗耐药的淋巴瘤细胞对利妥昔单抗介导的CDC敏感。在这里，我们进一步研究了rILYd4是否可以增敏肿瘤单抗介导的CDC，以及肿瘤单抗介导的CDC和rILYd4增强的肿瘤单抗介导的CDC是否与已知的参与利妥昔单抗活性的生物标志物CD20或CD59的表达相关。实验设计：利用利妥昔单抗耐药细胞系和原代CLL细胞来研究rILYd4与阿托单抗或利妥昔单抗联合应用的抗肿瘤效果。用碘化丙啶染色或阿拉玛蓝染色评价CDC的作用。结果：rILYd4在体外可增强ofatumab或rituximab介导的CDC对利妥昔单抗耐药淋巴瘤细胞和原代CLL细胞的杀伤作用。CLL细胞对ofatumumab介导的CDC效应的敏感性与CD20/CD59比值呈正相关，与CD59水平呈负相关。RILYd4增强CDC的程度与CLL细胞上CD59水平呈正相关。结论：rILYd4可能增强Ofatumab和Rituximab的抗癌活性，这些B细胞恶性肿瘤在以前基于抗体的治疗后复发。临床癌症资源；17(21)；6702-11。(C)2011年AACR。
Purpose: Ofatumumab is an anti-CD20 antibody recently approved for treatment of fludarabine and alemtuzumab refractory chronic lymphocytic leukemia (CLL); it mediates much stronger complement-dependent cytotoxicity (CDC) than rituximab. Human CD59, a key membrane complement regulator that inhibits CDC, is highly expressed in B-cell malignancies and its upregulation is an important determinant of the sensitivity of B-cell malignancies to rituximab treatment. Previously, we have shown that the potent CD59 inhibitor rILYd4 sensitizes rituximab-resistant lymphoma cells to rituximab-mediated CDC. Here, we further investigated whether rILYd4 can sensitize B-cell malignancies to ofatumumab-mediated CDC and whether either ofatumumab-mediated CDC or rILYd4-enhanced ofatumumab-mediated CDC correlates with CD20 or CD59 expression, known biomarkers involved in rituximab activity.Experimental Design: Rituximab-resistant cell lines and primary CLL cells were used to investigate the antitumor efficacy of the combination of rILYd4 with ofatumumab or rituximab. Propidium iodide staining or alamarBlue assay were used to evaluate the CDC effect. The levels of CD20 and CD59 on the cell membrane were analyzed by flow cytometry.Results: rILYd4 enhanced CDC effects mediated by ofatumumab or rituximab on rituximab-resistant lymphoma cells and primary CLL cells in vitro. The sensitivity to CDC effects mediated by ofatumumab positively correlated with the ratio of CD20/CD59 and negatively correlated with CD59 levels on CLL cells. The degree to which rILYd4 enhanced CDC correlated positively with the CD59 levels on CLL cells.Conclusions: These data suggest that rILYd4 may enhance the anticancer activity of ofatumumab and rituximab in B-cell malignancies that have relapsed after prior antibody-based therapies. Clin Cancer Res; 17(21); 6702-11. (C)2011 AACR.