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 D = 225 nM; IC 50 = 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.