Fc-dependent expression of CD137 on human NK cells: insights into "agonistic" effects of anti-CD137 monoclonal antibodies
Fc-dependent expression of CD137 on human NK cells: insights into "agonistic" effects of anti-CD137 monoclonal antibodies
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DOI：
10.1182/blood-2007-11-122465
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发表时间：
2008-08-01
期刊：
影响因子：
20.3
通讯作者：
Strome, Scott E.
中科院分区：
文献类型：
--
作者：
Lin, Wei;Voskens, Caroline J.;Strome, Scott E.
CD 137（4-伊布）是一种共刺激分子，可用于治疗癌症和自身免疫性疾病。尽管已知抗CD 137的激动性抗体（mAb）以自然杀伤（NK）细胞和T细胞依赖性方式增强鼠肿瘤的排斥，但对NK依赖性的机制知之甚少。在这项研究中，我们评估了嵌合抗人CD 137 mAb的2种不同糖型（无糖基化（GA）和低岩藻糖型（GG））与人NK细胞反应的能力。两种mAb与CD 137的结合相似，并部分阻断CD 137与CD 137配体之间的相互作用。然而，与GA mAb不同，固定化GG mAb激活NK细胞并增强CD 137表达。这些作用似乎依赖于Fc与INK细胞表面上推定的Fc受体的相互作用，因为CD 137表达仅需要GG的固定化Fc片段。此外，CD 137表达可以用针对非CD 137表位的抗体增强，并且表达水平与识别的Fc糖基化模式直接相关，以改善Fc与Fc γ受体的相互作用。我们的数据表明，CD 137可以增强NK细胞的Fc依赖性的方式和表达相关的表型和功能参数的激活。
CD137 (4-iBB) is a costimulatory molecule that can be manipulated for the treatment of cancer and autoimmune disease. Although it is known that agonistic antibodies (mAbs) against CD137 enhance the rejection of murine tumors in a natural killer (NK) cell- and T celldependent fashion, the mechanism for INK dependence is poorly understood. In this study, we evaluated the ability of 2 different glycoforms of a chimerized antihuman CD137 mAb, an aglycosylated (GA) and a low fucose form (GG), to react with human NK cells. Both mAbs bound similarly to CD137 and partially blocked the interaction between CD137 and CD137 ligand. However, unlike GA mAb, immobilized GG mAb activated NK cells and enhanced CD137 expression. These effects were seemingly dependent on Fc interaction with putative Fc receptors on the INK-cell surface, as only the immobilized Fc-fragment of GG was required for CD137 expression. Furthermore, CD137 expression could be enhanced with antibodies directed against non-CD137 epitopes, and the expression levels directly correlated with patterns of Fcglycosylation recognized to improve Fc interaction with Fcy receptors. Our data suggest that CD137 can be enhanced on NK cells in an Fc-dependent fashion and that expression correlates with phenotypic and functional parameters of activation.