Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange
Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange
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DOI：
10.1126/science.1144603
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发表时间：
2007-09-14
期刊：
影响因子：
56.9
通讯作者：
Parren, Paul W. H. I.
中科院分区：
文献类型：
--
作者：
Kolfschoten, Marijn van der Neut;Schuurman, Janine;Parren, Paul W. H. I.
抗体通过与先天免疫系统形成界面，在免疫中发挥核心作用，通常介导促炎活性。我们描述了一种新的翻译后修饰，导致免疫球蛋白G，同种型4 （IgG4）抗体的抗炎活性。IgG4抗体是动态分子，通过将重链和连接的轻链（半分子）与来自另一个分子的重-轻链对交换Fab臂，从而产生双特异性抗体。诱变研究表明，第三个恒定结构域对这种活性至关重要。IgG4 Fab臂交换的影响在实验性自身免疫性重症肌无力恒河猴模型中得到了证实。IgG4 Fab臂交换被认为是一个重要的生物学机制，为IgG4抗体的抗炎活性提供了基础。
Antibodies play a central role in immunity by forming an interface with the innate immune system and, typically, mediate proinflammatory activity. We describe a novel posttranslational modification that leads to anti-inflammatory activity of antibodies of immunoglobulin G, isotype 4 (IgG4). IgG4 antibodies are dynamic molecules that exchange Fab arms by swapping a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule, which results in bispecific antibodies. Mutagenesis studies revealed that the third constant domain is critical for this activity. The impact of IgG4 Fab arm exchange was confirmed in vivo in a rhesus monkey model with experimental autoimmune myasthenia gravis. IgG4 Fab arm exchange is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 antibodies.