Zhu Xueyong, Khalil Ahmed M, Piepenbrink Michael S, Yu Wenli, Ma Yao, Martinez-Sobrido Luis, Wilson Ian A, Kobie James J
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
contributed equally to the work: Xueyong Zhu, Ahmed M. Khalil, Michael S. Piepenbrink.
bioRxiv. 2025 Jul 1:2025.06.30.662356. doi: 10.1101/2025.06.30.662356.
Monoclonal antibodies (mAbs) that recognize and inhibit a diverse range of influenza viruses, although relatively rare, have been isolated following infection or vaccination. Study of their ontology and mechanisms of action informs universal vaccine and therapeutic development. We have previously described a potent and broad neuraminidase (NA)-neutralizing human mAb, 1122A11, that neutralizes a wide range of H3N2 viruses. Here, further characterization of 1122A11 reveals reactivity to cross-group influenza A virus NAs, including group-1 N1 and N8, and group-2 N2 and N3 NAs. Recent H3N2 viruses have acquired Asn245 glycosylation on the active site rim. Crystal structures of an N2 NA from A/Singapore/INFIMH-16-0019/2016 (H3N2) at 2.3 Å (apo) and 2.2 Å (Fab bound) resolution showed that 1122A11 binding causes local changes to the periphery of NA active site to accommodate the glycan. The CDRH3 of 1122A11 inserts into the active site and mimics the substrate sialic acid. We then determined that the ability of 1122A11 to protect from lethal challenge in mice is not dependent on Fc-effector function. These results highlight the therapeutic potential of 1122A11 as a broad protective anti-viral and reinforce pursuit of immunogen development of NA antibodies toward achieving more universal influenza protection.
尽管相对罕见，但在感染或接种疫苗后已分离出能识别并抑制多种流感病毒的单克隆抗体（mAb）。对其本体和作用机制的研究为通用疫苗和治疗方法的开发提供了信息。我们之前描述过一种强效且广谱的神经氨酸酶（NA）中和性人源单克隆抗体1122A11，它能中和多种H3N2病毒。在此，对1122A11的进一步表征揭示了其对跨组甲型流感病毒NA的反应性，包括第1组的N1和N8，以及第2组的N2和N3 NA。近期的H3N2病毒在活性位点边缘获得了天冬酰胺245糖基化。来自A/新加坡/INFIMH - 16 - 0019/2016（H3N2）的N2 NA在2.3 Å（无配体）和2.2 Å（结合Fab）分辨率下的晶体结构表明，1122A11的结合会导致NA活性位点周边发生局部变化以容纳聚糖。1122A11的互补决定区重链3（CDRH3）插入活性位点并模拟底物唾液酸。然后我们确定1122A11在小鼠中提供致死性攻击保护的能力不依赖于Fc效应器功能。这些结果突出了1122A11作为一种广谱保护性抗病毒药物的治疗潜力，并加强了对NA抗体免疫原开发的追求，以实现更广泛的流感防护。
