Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses
Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses
复制标题
轻链调节重链构象以改变针对甲型流感病毒的单克隆抗体的保护特性
DOI：
10.1038/s41421-019-0086-x
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发表时间：
2019-04-16
期刊：
影响因子：
33.5
通讯作者：
Gao, George Fu
中科院分区：
文献类型：
--
作者：
Xiao, Haixia;Guo, Tianling;Gao, George Fu
具有广泛中和广度的人源性单抗的分离为甲型流感病毒感染提供了一种有希望的对策。大多数甲型流感病毒的广泛中和抗体结合在血凝素的保守茎区域或受体结合腔上，这种相互作用是由重链主导的。然而，轻链对抗原的直接接触很少，甚至没有。在这里，我们报道了一种识别所有2型甲型流感病毒血凝素糖蛋白的H3-分支中和人单抗AF4H1K1。通过对一名H7N9感染患者的不同重链和轻链进行配对，基于下一代测序技术进行筛选，获得了这一人源性单抗。进一步的结构研究表明，轻链通过影响重链的局部构象来调节中和光谱，而不是直接与抗原相互作用。这些发现为理解轻链在抗原识别中的分子基础和探索策略提供了重要线索，特别是利用轻链修饰来开发针对甲型流感病毒和其他新出现的病毒的广泛保护性的单抗。
The isolation of human monoclonal antibodies with broadly neutralizing breadth can provide a promising countermeasure for influenza A viruses infection. Most broadly neutralizing antibodies against influenza A viruses bind to the conserved stem region or the receptor-binding cavity of hemagglutinin and the interaction is dominated by the heavy chain. The light chain, however, contributes few or no direct contacts to the antigen. Here we report an H3-clade neutralizing human monoclonal antibody, AF4H1K1, which recognizes the hemagglutinin glycoproteins of all group 2 influenza A viruses. This human monoclonal antibody has been obtained through the screening by pairing different heavy and light chains from an H7N9-infected patient based on the next-generation sequencing technology. Further structural studies revealed that light chains modulate the neutralizing spectrum by affecting the local conformation of heavy chains, instead of direct interaction with the antigen. These findings provide important clues to understand the molecular basis of light chains in antigen recognition and to explore the strategies in particular of the use of light chain modification to develop broadly protective monoclonal antibodies against influenza A viruses and other emerging viruses.