Plant-produced anti-dengue virus monoclonal antibodies exhibit reduced antibody-dependent enhancement of infection activity
Plant-produced anti-dengue virus monoclonal antibodies exhibit reduced antibody-dependent enhancement of infection activity
复制标题
植物生产的抗登革病毒单克隆抗体表现出较低的抗体依赖性感染活性增强效应
DOI：
10.1099/jgv.0.000635
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发表时间：
2016-12-01
影响因子：
3.8
通讯作者：
Chen, Qiang
中科院分区：
文献类型：
--
作者：
Dent, Matthew;Hurtado, Jonathan;Chen, Qiang
mAb E60具有成为理想的治疗分子的潜力，因为它有效地中和登革病毒（DENV）的所有四种血清型。然而，大肠杆菌细胞产生的E60表现出抗体依赖性的感染增强（ADE）活性，使其在体内无效，治疗的动物更容易在继发感染期间发展更严重的疾病。在这项研究中，我们评估了一种基于植物的表达系统，用于生产治疗上合适的E60。mAb在本氏烟草WT和Delta XFT系（缺乏植物特异性N-聚糖残基的糖基化突变体）中瞬时表达。mAb在叶片中有效表达和组装，并表现出高度同源的N-糖基化特征，即GnGnXF（3）或GnGn结构，取决于表达宿主。两种E60糖变体与它们的大肠杆菌细胞产生的对应物相比，表现出对DENV血清型2和4的等效抗原结合特异性和体外中和效力。相比之下，植物产生的E60在表达Fc γ受体的人细胞中表现出降低的ADE活性。我们的研究结果表明，植物产生的抗体能够最大限度地减少ADE，这可能会导致开发针对DENV和其他ADE易感病毒疾病的安全和高效的基于抗体的治疗方法。我们的研究提供了迄今为止未知的mAb N-糖基化和ADE之间的关系，这有助于我们了解抗体的糖部分如何调节Fc介导的功能和病毒的发病机制。
The mAb E60 has the potential to be a desirable therapeutic molecule since it efficiently neutralizes all four serotypes of dengue virus (DENV). However, mammalian-cell-produced E60 exhibits antibody-dependent enhancement of infection (ADE) activity, rendering it inefficacious in vivo, and treated animals more susceptible to developing more severe diseases during secondary infection. In this study, we evaluated a plant-based expression system for the production of therapeutically suitable E60. The mAb was transiently expressed in Nicotiana benthamianaWT and a Delta XFT line, a glycosylation mutant lacking plant-specific N-glycan residues. The mAb was efficiently expressed and assembled in leaves and exhibited highly homogenous N-glycosylation profiles, i.e. GnGnXF(3) or GnGn structures, depending on the expression host. Both E60 glycovariants demonstrated equivalent antigen-binding specificity and in vitro neutralization potency against DENV serotypes 2 and 4 compared with their mammalian-cell-produced counterpart. By contrast, plant-produced E60 exhibited reduced ADE activity in Fc gamma receptor expressing human cells. Our results suggest the ability of plant-produced antibodies to minimize ADE, which may lead to the development of safe and highly efficacious antibody-based therapeutics against DENV and other ADE-prone viral diseases. Our study provides so far unknown insight into the relationship between mAb N-glycosylation and ADE, which contributes to our understanding of how sugar moieties of antibodies modulate Fc-mediated functions and viral pathogenesis.