Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density
Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density
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DOI：
10.1158/1078-0432.ccr-04-2263
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发表时间：
2005-03-15
影响因子：
11.5
通讯作者：
Shitara, K
中科院分区：
文献类型：
--
作者：
Niwa, R;Sakurada, M;Shitara, K
目的：最近的研究表明，从人IgG1抗体的寡糖中去除岩藻糖可以通过改善IgG1与Fc-Gamma RIIIa的结合而显著增强抗体依赖的细胞毒性(ADCC)。实验设计：以表达水平不同的外源性人CC趋化因子受体4或人CD20的EL4细胞为靶细胞，检测针对这些抗原的嵌合IgG1抗体的岩藻糖变异体的ADCC。我们进一步研究了IgG1与自然杀伤(NK)细胞的结合以及在ADCC诱导过程中NK细胞的活化，以阐明低岩藻糖IgG1诱导低抗原表达的靶细胞ADCC的机制。结果：低岩藻糖IgG1在低抗原密度下显示出有效的ADCC，而相应的高岩藻糖IgG1在低抗原密度下不能诱导可测的ADCC。定量分析表明，去岩藻糖可以减少靶细胞上恒定程度诱导ADCC所需的抗原量，CC趋化因子受体4和CD20的抗原量分别减少10倍和3倍。用聚集性抗原连接IgG1可增加其与NK细胞的结合，尤其是对低岩藻糖类的IgG1。在抗体和靶细胞同时存在的情况下，激活标记CD69上调NK细胞，特别是CD56(Dim)亚群。结论：从IgG1中去除岩藻糖可以通过有效地募集和激活NK细胞来减少诱导ADCC所需的抗原量。
Purpose: Recent studies have revealed that fucose removal from the oligosaccharides of human IgG1 antibodies results in a significant enhancement of antibody-dependent cellular cytotoxicity (ADCC) via improved IgG1 binding to Fc gamma RIIIa. In this report, we investigated the relationship between enhanced ADCC and antigen density on target cells using IgG1 antibodies with reduced fucose.Experimental Design: Using EL4 cell-derived transfectants with differential expression levels of exogenous human CC chemokine receptor 4 or human CD20 as target cells, ADCC of fucose variants of chimeric IgG1 antibodies specific for these antigens were measured. We further investigated IgG1 binding to natural killer (NK) cells and NK cell activation during ADCC induction to elucidate the mechanism by which low-fucose IgG1 induces ADCC upon target cells with low antigen expression.Results: Low-fucose IgG1s showed potent ADCC at low antigen densities at which their corresponding high-fucose counterparts could not induce measurable ADCC. The quantitative analysis revealed that fucose depletion could reduce the antigen amount on target cells required for constant degrees of ADCC induction by 10-fold for CC chemokine receptor 4 and 3-fold for CD20. IgG1 binding to NK cells was increased by ligating IgG1 with clustered antigen, especially for low-fucose IgG1. Up-regulation of an activation marker, CD69, on NK cells, particularly the CD56(dim) subset, in the presence of both the antibody and target cells was much greater for the low-fucose antibodies.Conclusions: Our data showed that fucose removal from IgG1 could reduce the antigen amount required for ADCC induction via efficient recruitment and activation of NK cells.