2026-02-26 住友ファーマ株式会社
＜関連情報＞
- https://www.sumitomo-pharma.co.jp/news/20260226-2.html
- https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011554
融合後安定化エピトープを標的とするインフルエンザウイルスヘマグルチニン抗体のグループ間認識の構造的基礎 Structural basis for cross-group recognition of an influenza virus hemagglutinin antibody that targets postfusion stabilized epitope
Keisuke Tonouchi,Yu Adachi,Tateki Suzuki,Daisuke Kuroda,Ayae Nishiyama,Kohei Yumoto,Haruko Takeyama,Tadaki Suzuki,Takao Hashiguchi,Yoshimasa Takahashi
PLOS Pathogens Published: August 9, 2023
DOI:https://doi.org/10.1371/journal.ppat.1011554
Abstract
Plasticity of influenza virus hemagglutinin (HA) conformation increases an opportunity to generate conserved non-native epitopes with unknown functionality. Here, we have performed an in-depth analysis of human monoclonal antibodies against a stem-helix region that is occluded in native prefusion yet exposed in postfusion HA. A stem-helix antibody, LAH31, provided IgG Fc-dependent cross-group protection by targeting a stem-helix kinked loop epitope, with a unique structure emerging in the postfusion state. The structural analysis and molecular modeling revealed key contact sites responsible for the epitope specificity and cross-group breadth that relies on somatically mutated light chain. LAH31 was inaccessible to the native prefusion HA expressed on cell surface; however, it bound to the HA structure present on infected cells with functional linkage to the Fc-mediated clearance. Our study uncovers a novel non-native epitope that emerges in the postfusion HA state, highlighting the utility of this epitope for a broadly protective antigen design.
Author summary
Induction of broadly protective antibodies is a clue to combat the antigenic variation of influenza virus. In this context, directing the antibody specificity toward the conserved hemagglutinin (HA) epitopes is a rational approach; however, it is hampered by virus strategies to hide the vulnerable sites. Here, we show a novel non-native epitope that emerges in the postfusion HA state with unique structure, denoted as kinked loop-helix. Antibody toward this epitope is accessible to HA on infected cells, demonstrating an exposure of the vulnerable sites during viral replication. In-depth structural analysis uncovers how antibody adapts to the conserved non-native epitope and provide cross-group protection, with an implication to rational design of broadly protective immunogens.
