Nonfucosylated therapeutic IgG1 antibody can evade the inhibitory effect of serum immunoglobulin g on antibody-dependent cellular cytotoxicity through its high binding to FcγRIIIa
Nonfucosylated therapeutic IgG1 antibody can evade the inhibitory effect of serum immunoglobulin g on antibody-dependent cellular cytotoxicity through its high binding to FcγRIIIa
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DOI：
10.1158/1078-0432.ccr-05-2619
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发表时间：
2006-05-01
影响因子：
11.5
通讯作者：
Satoh, M
中科院分区：
文献类型：
--
作者：
Iida, S;Misaka, H;Satoh, M
目的：最近的研究表明，岩藻糖基化治疗性IgG 1需要高浓度来补偿内源性人血浆IgG对抗体依赖性细胞毒性（ADCC）的Fc γ RIIIa竞争性抑制。在此，我们研究了非岩藻糖基化治疗性IgG 1的ADCC是否也以与岩藻糖基化IgG 1相同的方式受到血浆IgG的影响。实验设计：通过将人全血与非岩藻糖基化和/或岩藻糖基化抗CD 20 IgG 1利妥昔单抗孵育诱导对CD 20（+）人B细胞的体外ADCC，并通过使用流式细胞术测量剩余的CD 19（+）人B细胞来定量。在存在血浆IgG的情况下，非岩藻糖基化抗CD 20显示出比其岩藻糖基化对应物显著更高（基于EC 50超过100倍）的离体B细胞耗竭活性。岩藻糖基化抗CD 20在血浆中的疗效大大降低，导致需要高浓度（超过1.0 μ g/mL）才能达到饱和疗效。相比之下，非岩藻糖基化抗CD 20在较低浓度（0.01-0.1 μ g/mL）下达到饱和ADCC，通过改善Fc γ RIIIa结合，在所有9名供体中的疗效远高于岩藻糖基化抗CD 20。值得注意的是，添加岩藻糖基化抗CD 20抑制了非岩藻糖基化抗CD 20的高疗效。因此，非岩藻糖基化和岩藻糖基化抗CD 20的1：9混合物（10 μ g/mL）的疗效劣于非岩藻糖基化抗CD 20单独稀释1，000倍（0.01 μ g/mL）的疗效。结论：我们的数据显示，非岩藻糖基化IgG 1（不包括岩藻糖基化对应物）可通过其高Fc γ RIIIa结合逃避血浆IgG对ADCC的抑制作用。因此，非岩藻糖基化IgG 1通过在人体内以低剂量显著增强ADCC表现出强大的治疗潜力。
Purpose: Recent studies have revealed that fucosylated therapeutic IgG1s need high concentrations to compensate for Fc gamma RIIIa-competitive inhibition of antibody-dependent cellular cytotoxicity (ADCC) by endogenous human plasma IgG. Here, we investigated whether ADCC of nonfucosylated therapeutic IgG1 is also influenced by plasma IgG in the same way as fucosylated IgG1s.Experimental Design: Ex vivo ADCC upon CD20(+) human B cells was induced by incubation of human whole blood with nonfucosylated and/or fucosylated anti-CD20 IgG1s rituximab, and quantified by measuring the remaining CD19(+) human B cells using flow cytometry.Results: Nonfucosylated anti-CD20 showed markedly higher (over 100-fold based on EC50) ex vivo B-cell depletion activity than its fucosylated counterpart in the presence of plasma IgG. The efficacy of fucosylated anti-CD20 was greatly diminished in plasma, resulting in the need for a high concentration (over 1.0 mu g/mL) to achieve saturated efficacy. In contrast, nonfucosylated anti-CD20 reached saturated ADCC at lower concentrations (0.01-0.1 mu g/mL) with much higher efficacy than fucosylated anti-CD20 in all nine donors through improved Fc gamma RIIIa binding. Noteworthy, the high efficacy of nonfucosylated anti-CD20 was inhibited by addition of fucosylated anti-CD20. Thus, the efficacy of a 1:9 mixture (10 mu g/mL) of nonfucosylated and fucosylated anti-CD20s was inferior to that of a 1,000-fold dilution (0.01 mu g/mL) of nonfucosylated anti-CD20 alone.Conclusions: Our data showed that nonfucosylated IgG1, not including fucosylated counterparts, can evade the inhibitory effect of plasma IgG on ADCC through its high Fc gamma RIIIa binding. Hence, nonfucosylated IgG1 exhibits strong therapeutic potential through dramatically enhanced ADCC at low doses in humans in vivo.