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首页> 美国卫生研究院文献>Clinical and Experimental Immunology >STIM1 knock‐down decreases the affinity of obinutuzumab for CD20 by altering CD20 localization to Triton‐soluble membrane
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STIM1 knock‐down decreases the affinity of obinutuzumab for CD20 by altering CD20 localization to Triton‐soluble membrane

机译：通过将CD20定位改变为Triton-Soluble膜Stim1击倒降低了ObInutuzumab对CD20的亲和力

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摘要

Obinutuzumab is thought to exert its effects through its high antibody‐dependent cellular cytotoxicity (ADCC) via glyco‐engineering of the Fc region. In addition, obinutuzumab causes direct binding‐induced cell death (DCD) only by specifically binding to its target CD20, a Ca2+ channel. However, the specific features of CD20 related to obinutuzumab binding‐induction of cell death are not clearly understood. In this study, we evaluated the relationship between the Ca2+ channel features of CD20 as a store‐operated Ca2+ channel (SOC) and obinutuzumab binding‐induced cell death. Ca2+ channel function and biochemical analysis revealed that CD20 is an Orai1‐ and stromal interaction molecule (STIM1)‐dependent Ca2+ pore. However, binding of obinutuzumab on CD20 did not have any effect on Ca2+ influx activity of CD20; the direct cell death rate mediated by obinutuzumab binding was almost equivalent with or without the extracellular Ca2+ condition. Given the apparent interaction between STIM1 and CD20, we observed Triton‐X solubilized obinutuzumab‐bound CD20 accompanied by STIM1. Subsequently, obinutuzumab binding and cell death were decreased by STIM1 knock‐down in Ramos B cells. Thus, STIM1 directly contributes to cell death by increasing the affinity of cells for obinutuzumab by transferring CD20 to the Triton‐soluble membrane region.
机译：ObInutuzumab被认为是通过Fc区的Glyco-Enginege通过其高抗体依赖性细胞细胞毒性（ADCC）发挥其效果。此外，ObInutuzumab仅通过特异性结合其靶CD20，CA2 +通道使得直接结合诱导的细胞死亡（DCD）。然而，没有清楚地理解与obInutuzumab结合诱导的CD20相关的特定特征。在这项研究中，我们评估了CD20的CA2 +信道特征与存储器操作的CA2 +通道（SOC）和obinutuzumab结合诱导的细胞死亡的关系。 CA2 +通道功能和生物化学分析显示CD20是ORAI1和基质相互作用分子（STIM1） - 依赖性CA2 +孔。然而，ObInutuzumab对CD20的结合对CD20的CA2 +流入活性没有任何影响;由ObInutuzumab结合介导的直接细胞死亡率几乎与细胞外CA2 +条件相当于等同物。鉴于STIM1和CD20之间的表观相互作用，我们观察到TRITON-X Solubilized ObInutuzumab-结合的CD20伴有SIT溶液。随后，在RAMOS B细胞中通过STIM1敲低降低ObInutuzumab结合和细胞死亡。因此，通过将CD20转移到Triton-Soluble膜区，通过增加细胞的亲和力直接有助于细胞死亡。

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