IgG‐Bridging–Seeded Synergistic Aggregation of SARS‐CoV‐2 Spikes Underlies Potent Neutralization by a Low‐Affinity Antibody

Mechanistic studies of viral neutralization typically prioritize high-affinity antibodies, relegating low-affinity binders to the sidelines. P5‑1C8, a Class 1 SARS-CoV-2 antibody that exemplifies this underexplored "low‑affinity yet high‑potency" phenotype is reported, retaining strong neutralization of Omicron JN.1 despite markedly weakened trimer binding (K<sub>D</sub> = 225 nM; IC<sub>50</sub> = 0.06 nM). Structural and biophysical analyses reveal that P5-1C8 engages WT and BA.1 spikes through canonical intra-spike bivalency, but with JN.1 it induces aggregation. Using virion-like nanoparticles displaying multiple spikes, it is shown that IgG remains bound with no detectable dissociation and triggers pronounced aggregation. Coarse-grained molecular dynamics delineate the stepwise pathway in which weak IgG-spike contacts seed aggregation via transient inter-spike bridging. Together, these findings establish the first mechanistic framework demonstrating how weak-binding antibodies can nonetheless achieve potent neutralization through higher-order aggregation, thereby expanding the conceptual landscape of antibody function and opening new directions for antibody evaluation and design.

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Publication Details

Journal
Advanced Science
Published
2025-12-07
DOI
https://doi.org/10.1002/advs.202517192
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.00

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article

IgG‐Bridging–Seeded Synergistic Aggregation of SARS‐CoV‐2 Spikes Underlies Potent Neutralization by a Low‐Affinity Antibody

Yiqian Huang, Linqi Zhang, Xiaojing Pan, Yuanchen Dong et al.
Advanced Science
SARS-CoV-2 and COVID-19 Research
article

IgG‐Bridging–Seeded Synergistic Aggregation of SARS‐CoV‐2 Spikes Underlies Potent Neutralization by a Low‐Affinity Antibody

Yiqian Huang, Linqi Zhang, Xiaojing Pan, Yuanchen Dong, Yifan Jiang, Jinqian Li, Li‐Tang Yan, Zelin Shan, Guizhi Dong, Ziheng Li, Xinquan Wang, Yuhe R. Yang, Fenglin Guo, Chunying Chen, Shilong Fan, Deli Huang, Xiaobin Dai, Qi Zhang, Zhihua Liu, Kang Zhang, Dongsheng Liu, Jiayi Li, Yuliang Zhao, Peng Chen, Hanjun Zhao, Xuanyu Nan, Yuanfang Chen, Nonghua Lv, Liang Chen, Hu Xu
article en

Abstract

Mechanistic studies of viral neutralization typically prioritize high-affinity antibodies, relegating low-affinity binders to the sidelines. P5‑1C8, a Class 1 SARS-CoV-2 antibody that exemplifies this underexplored "low‑affinity yet high‑potency" phenotype is reported, retaining strong neutralization of Omicron JN.1 despite markedly weakened trimer binding (K<sub>D</sub> = 225 nM; IC<sub>50</sub> = 0.06 nM). Structural and biophysical analyses reveal that P5-1C8 engages WT and BA.1 spikes through canonical intra-spike bivalency, but with JN.1 it induces aggregation. Using virion-like nanoparticles displaying multiple spikes, it is shown that IgG remains bound with no detectable dissociation and triggers pronounced aggregation. Coarse-grained molecular dynamics delineate the stepwise pathway in which weak IgG-spike contacts seed aggregation via transient inter-spike bridging. Together, these findings establish the first mechanistic framework demonstrating how weak-binding antibodies can nonetheless achieve potent neutralization through higher-order aggregation, thereby expanding the conceptual landscape of antibody function and opening new directions for antibody evaluation and design.

Advanced ScienceVol. 13(11)
Salk Institute for Biological Studies (US), Shanghai Medical College of Fudan University (CN), Hong Kong Polytechnic University (HK), Shenzhen Institute of Information Technology (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Hong Kong Science and Technology Parks Corporation (HK), Zhejiang Cancer Hospital (CN), Shenzhen Bay Laboratory (CN), Tsinghua–Berkeley Shenzhen Institute (CN), Ministry of Education (KR), National Institute of Clean and Low-Carbon Energy (CN), Lanzhou City University (CN), National Center for Nanoscience and Technology (CN), Bio-Medical Science (South Korea) (KR), Ministry of Education (ET), Institute of Chemistry (CN), University of Chinese Academy of Sciences (CN), Zhejiang University (CN), Lanzhou University (CN), University of Hong Kong (HK), Tsinghua University (CN)
National Science Foundation, National Natural Science Foundation of China, Chinese Academy of Sciences
Openalex Percentile: Top 55%
SARS-CoV-2 and COVID-19 Research
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