Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; College of Life Sciences, Agricultural University of Hebei, Baoding, Hebei 071001, China.
Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, MD 21702, USA.
Cell Host Microbe. 2017 Oct 11;22(4):471-483.e5. doi: 10.1016/j.chom.2017.08.011. Epub 2017 Sep 28.
The H7N9 influenza virus causes high-mortality disease in humans but no effective therapeutics are available. Here we report a human monoclonal antibody, m826, that binds to H7 hemagglutinin (HA) and protects against H7N9 infection. m826 binds to H7N9 HA with subnanomolar affinity at acidic pH and 10-fold lower affinity at neutral pH. The high-resolution (1.9 Å) crystal structure of m826 complexed with H7N9 HA indicates that m826 binds an epitope that may be fully exposed upon pH-induced conformational changes in HA. m826 fully protects mice against lethal challenge with H7N9 virus through mechanisms likely involving antibody-dependent cell-mediated cytotoxicity. Interestingly, immunogenetic analysis indicates that m826 is a germline antibody, and m826-like sequences can be identified in H7N9-infected patients, healthy adults, and newborn babies. These m826 properties offer a template for H7N9 vaccine immunogens, a promising candidate therapeutic, and a tool for exploring mechanisms of virus infection inhibition by antibodies.
H7N9 流感病毒可导致人类高死亡率疾病，但目前尚无有效的治疗方法。本文报道了一种人源单克隆抗体 m826，它能与 H7 血凝素（HA）结合，预防 H7N9 感染。m826 在酸性 pH 值下以纳摩尔级亲和力与 H7N9 HA 结合，在中性 pH 值下亲和力降低 10 倍。m826 与 H7N9 HA 的高分辨率（1.9Å）晶体结构表明，m826 结合的表位在 pH 诱导的 HA 构象变化时可能完全暴露。m826 通过可能涉及抗体依赖的细胞介导的细胞毒性的机制，完全保护小鼠免受 H7N9 病毒的致死性攻击。有趣的是，免疫遗传学分析表明，m826 是一种胚系抗体，在 H7N9 感染患者、健康成年人和新生儿中可以识别出 m826 样序列。这些 m826 特性为 H7N9 疫苗免疫原、有前途的候选治疗药物以及探索抗体抑制病毒感染机制的工具提供了模板。
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