Gilchuk Iuliia M, Dong Jinhui, Irving Ryan P, Buchman Cameron D, Armstrong Erica, Turner Hannah L, Li Sheng, Ward Andrew B, Carnahan Robert H, Crowe James E
The Vanderbilt Center for Antibody Therapeutics, Vanderbilt Medical Center, Nashville, Tennessee, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA.
JCI Insight. 2025 Jun 5;10(13). doi: 10.1172/jci.insight.186182. eCollection 2025 Jul 8.
H7N9 avian influenza virus is a zoonotic influenza virus of public health concern, with a 39% mortality rate in humans. H7N9-specific prevention or treatments for humans have not been approved. We previously isolated a human monoclonal antibody (mAb) designated H7-235 that broadly reacts to diverse H7 viruses and neutralizes H7N9 viruses in vitro. Here, we report the crystal structure of H7 HA1 bound to the fragment antigen-binding region (Fab) of recombinant H7-235 (rH7-235). The crystal structure revealed that rH7-235 recognizes residues near but outside of the receptor binding site (RBS). Nevertheless, the rH7-235 IgG potently inhibits hemagglutination mediated by H7N9 viruses due to avidity effect and Fc steric hindrance. This mAb prophylactically protects mice against weight loss and death caused by challenge with lethal H7N9 viruses in vivo. rH7-235 mAb neutralizing activity alone is sufficient for protection when used at a high dose in a prophylactic setting. This study provides insights into mechanisms of viral neutralization by protective, broadly reactive anti-H7 antibodies, informing the rational design of therapeutics and vaccines against H7N9 influenza virus.
H7N9禽流感病毒是一种引起公众健康关注的人畜共患流感病毒，在人类中的死亡率为39%。针对人类的H7N9特异性预防措施或治疗方法尚未获批。我们之前分离出一种名为H7-235的人源单克隆抗体（mAb），它能广泛地与多种H7病毒发生反应，并在体外中和H7N9病毒。在此，我们报告了与重组H7-235（rH7-235）的片段抗原结合区（Fab）结合的H7 HA1的晶体结构。晶体结构显示，rH7-235识别受体结合位点（RBS）附近但在其外的残基。然而，由于亲和力效应和Fc空间位阻，rH7-235 IgG能有效抑制H7N9病毒介导的血凝反应。在体内，这种单克隆抗体可预防性保护小鼠免受致死性H7N9病毒攻击导致的体重减轻和死亡。当在预防性给药时以高剂量使用，单独的rH7-235 mAb中和活性就足以提供保护。这项研究为具有保护性、广泛反应性的抗H7抗体的病毒中和机制提供了见解，为针对H7N9流感病毒的治疗药物和疫苗的合理设计提供了依据。
