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IgG-Bridging–Seeded Synergistic Aggregation of SARS-CoV-2 Spikes Underlies Potent Neutralization by a Low-Affinity Antibody
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DOI：10.1002/advs.202517192.png)
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Abstract
En 中文
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 (KD = 225 nM; IC50 = 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.
Keywords:
full-length IgG
low-affinity
potent neutralization
multivalent aggregation
virion-like nanoparticles
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