Ofatumumab Is More Efficient than Rituximab in Lysing B Chronic Lymphocytic Leukemia Cells in Whole Blood and in Combination with Chemotherapy

奥图穆马 氟达拉滨 CD20 慢性淋巴细胞白血病 全血 CD59型 美罗华 免疫学 细胞毒性 流式细胞术 补体系统 医学 白血病 药理学 癌症研究 抗体 化学 化疗 内科学 生物化学 体外 环磷酰胺
作者
Luca Bologna,Elisa Gotti,Fabio Da Roit,Tamara Intermesoli,Alessandro Rambaldi,Martino Introna,Josée Golay
出处
期刊:Journal of Immunology [American Association of Immunologists]
卷期号:190 (1): 231-239 被引量:95
标识
DOI:10.4049/jimmunol.1202645
摘要

Abstract Ofatumumab (OFA) is a human anti-CD20 Ab approved for treatment of fludarabine-refractory B chronic lymphocytic leukemia (B-CLL). The efficacy of different immunotherapeutic strategies is best investigated in conditions that are as physiologic as possible. We have therefore compared the activity OFA and rituximab (RTX), alone or in combination with chemotherapeutic agents in unmanipulated whole blood assays, using flow cytometry. OFA (10–100 μg/ml) lysed B-CLL targets in whole blood more efficiently and with faster kinetics than RTX, with a mean 56% lysis at 24 h compared with 16%. This activity of OFA was fully complement dependent, as shown by >99% inhibition by anti-C5 Ab eculizumab and a lack of NK cell activation in whole blood. OFA-mediated NK cell activation was blocked by complement. OFA-mediated lysis could be increased an additional 15% by blocking CD55 and CD59 complement inhibitors. Interestingly, OFA-mediated lysis correlated significantly with CD20 expression levels (r2 = 0.79). OFA showed overlapping dose response curves similar to those for RTX in phagocytosis assays using either human macrophages or neutrophils. However, phagocytosis was inhibited in the presence of serum or whole blood. Finally, combined treatment with mafosfamide and fludarabine showed that these therapeutic drugs are synergistic in B-CLL whole blood assays and show superior activity when combined with OFA compared with RTX. These results confirm in B-CLL samples and in physiologic conditions the superior complement mediated cytotoxicity induced by OFA alone compared with RTX, the lack of NK cell activation, and phagocytosis in these conditions and suggest effective chemoimmunotherapy strategies using this new generation anti-CD20 Ab.
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