针对 2 型流感病毒的中和作用的常见解决方案。

A common solution to group 2 influenza virus neutralization.

机构信息

Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, 2333 CN, Leiden, The Netherlands.

出版信息

Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):445-50. doi: 10.1073/pnas.1319058110. Epub 2013 Dec 11.

Abstract

The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.

摘要

广谱中和抗体(bnAbs)的发现和鉴定为开发基于单克隆抗体(mAb)的免疫疗法和通用流感疫苗设计带来了希望。此前已经鉴定出一种针对 2 型流感病毒的人类 bnAb(CR8020),它特异性识别血凝素(HA)茎底部的高度保守表位,对 H3、H7 和 H10 病毒具有中和活性。在这里,我们报告了第二种 2 型 bnAb,CR8043,它源自另一个编码高度不同氨基酸序列的种系基因。CR8043 在体外对 H3 和 H10 病毒具有中和活性,并能保护小鼠免受致死剂量的 H3N2 和 H7N7 病毒的攻击。CR8043-H3 HA 复合物的晶体结构和 EM 重建表明,CR8043 结合到与 CR8020 表位相似的位点,但采用不同的接近角度和不同的相互作用。另一种针对 2 型茎部表位的抗体的鉴定表明,这个保守的脆弱部位具有很大的潜力,可以设计治疗方法和疫苗。

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