Antibody with an engineered Fc region as a therapeutic agent against dengue virus infection
Antibody with an engineered Fc region as a therapeutic agent against dengue virus infection
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DOI：
10.1016/j.antiviral.2015.10.012
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发表时间：
2015-12-01
影响因子：
7.6
通讯作者：
Kurosu, Takeshi
中科院分区：
文献类型：
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作者：
Ramadhany, Ririn;Hirai, Itaru;Kurosu, Takeshi
抗体依赖增强(ADE)的登革病毒(DENV)传染性被认为在严重的登革热疾病中起关键作用。当原感染产生的预先存在的亚中和抗DENV抗体(Ab)遇到与初始感染不同的DENV血清型并形成免疫复合物时，就会发生这种情况，从而使Fc-γ受体携带细胞能够有效地感染。然而，抗体在患者继发感染过程中所起的确切作用仍不清楚。我们以前从一例DENV感染患者中获得了广泛交叉反应的中和人抗DENV包膜(E)抗体(HuMAb)D23-1G7C2-IgG1，但D23-1G7C2-IgG1具有ADE活性。为了能够降低ADE活性，我们交换了D23-1G7C2的Fc区，以产生携带其他三个免疫球蛋白亚类(IgG2-4)的抗体。此外，N297A突变被引入到D23-1G7C2-IgG1中，该突变可降低IgG1Fc区与Fcγ受体的亲和力。将D23-1G7C2-IgG1替换为IgG2或IgG4亚类可降低Fc-Gamma RI和Fc-Gamma RII-THP-1细胞的ADE活性。相比之下，在携带Fc-Gamma RII的K562细胞中，改变为IgG2可增加ADE活性。将N297A突变导入D23-1G7C2-IgG1后，两种细胞的ADE活性均显著降低。与D23-1G7C2-IgG1相比，D23-1G7C2-IgG1-N297A在日本脑炎病毒中携带DENV-2 PRME的重组嵌合DENV感染的干扰素-α/β/伽马受体敲除小鼠中的保护作用较弱(分别为80%和40%)。这些观察结果为重组抗体作为治疗药物的使用提供了有价值的信息。(C)2015爱思唯尔B.V.保留所有权利。
Antibody-dependent enhancement (ADE) of dengue virus (DENV) infectivity is thought to play a crucial role in severe dengue disease. It occurs when pre-existing sub-neutralizing anti-DENV antibody (Ab) produced from a primary infection encounters a DENV serotype different from that of the initial infection and forms immune complexes, which enable the efficient infection of Fc gamma receptor-bearing cells. However, the exact role played by Abs during a secondary infection of patients remains unknown. We previously obtained a broadly cross-reactive neutralizing IgG1 human monoclonal anti-DENV envelope (E) Ab (HuMAb) D23-1G7C2-IgG1 from a DENV-infected patient; however, D23-1G7C2-IgG1 had ADE activity. With the aim of being able to reduce the ADE activity, we exchanged the Fc region of D23-1G7C2 to generate Abs bearing each of the three other IgG subclasses (IgG2-4). In addition, N297A, a mutation known to reduce the affinity of the IgG1 Fc region for Fc gamma receptors, was introduced into D23-1G7C2-IgGl. Swapping D23-1G7C2-IgG1 to IgG2 or IgG4 subclasses reduced ADE activity in Fc gamma RI and Fc gamma RII-bearing THP-1 cells. By contrast, in Fc gamma RII-bearing K562 cells, the change to IgG2 increased ADE activity. Introducing the N297A mutation into D23-1G7C2-IgG1 resulted in a marked reduction in ADE activity in both cell types. Compared to D23-1G7C2-IgGl, D23-1G7C2-IgG1-N297A was less protective in IFN-alpha/beta/gamma receptor knockout mice infected with a lethal dose of recombinant chimeric DENV, carrying prME of DENV-2 in Japanese encephalitis virus (80% vs. 40% survival, respectively). These observations provide valuable information regarding the use of recombinant Abs as therapeutics. (C) 2015 Elsevier B.V. All rights reserved.