Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, 2333 CN, Leiden, The Netherlands.
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):445-50. doi: 10.1073/pnas.1319058110. Epub 2013 Dec 11.
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.
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。
