Lee Peter S, Ohshima Nobuko, Stanfield Robyn L, Yu Wenli, Iba Yoshitaka, Okuno Yoshinobu, Kurosawa Yoshikazu, Wilson Ian A
1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Division of Antibody Project, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Nat Commun. 2014 Apr 10;5:3614. doi: 10.1038/ncomms4614.
Influenza viruses present a significant health challenge each year, as in the H3N2 epidemic of 2012-2013. Here we describe an antibody, F045-092, that possesses broadly neutralizing activity against the entire H3 subtype and accommodates the natural variation and additional glycosylation in all strains tested from 1963 to 2011. Crystal structures of F045-092 in complex with HAs from 1975 and 2011 H3N2 viruses reveal the structural basis for its neutralization breadth through insertion of its 23-residue HCDR3 into the receptor-binding site that involves striking receptor mimicry. F045-092 extends its recognition to divergent subtypes, including H1, H2 and H13, using the enhanced avidity of its IgG to overcome lower-affinity Fab binding, as observed with other antibodies that target the receptor-binding site. This unprecedented level of antibody cross-reactivity against the H3 subtype can potentially inform on development of a pan-H3 vaccine or small-molecule therapeutics.
流感病毒每年都构成重大的健康挑战，如2012 - 2013年的H3N2疫情。在此，我们描述了一种抗体F045 - 092，它对整个H3亚型具有广泛的中和活性，并且能够适应1963年至2011年测试的所有毒株中的自然变异和额外糖基化。F045 - 092与1975年和2011年H3N2病毒的血凝素（HA）形成复合物的晶体结构揭示了其通过将23个残基的重链互补决定区3（HCDR3）插入涉及显著受体模拟的受体结合位点来实现中和广度的结构基础。F045 - 092利用其IgG增强的亲和力来克服较低亲和力的Fab结合，将其识别扩展到不同的亚型，包括H1、H2和H13，这与其他靶向受体结合位点的抗体情况相同。这种针对H3亚型前所未有的抗体交叉反应水平可能为通用H3疫苗或小分子疗法的开发提供信息。
