IgG-Bridging-Seeded Synergistic Aggregation of SARS-CoV-2 Spikes Underlies Potent Neutralization by A Low-Affinity Antibody

Lv, N.; Chen, P.; Dai, X.; Xu, H.; Li, Z.; Shan, Z.; Li, J.; Guo, F.; Chen, Y.; Huang, Y.; Dong, G.; Jiang, Y.; Chen, L.; Nan, X.; Zhao, H.; Zhang, K.; Fan, S.; Dong, Y.; Liu, D.; wang, x.; Huang, D.; Pan, X.; Chen, C.; Liu, Z.; Yan, L.-T.; Zhang, Q.; Zhang, L.; Zhao, Y.; Yang, Y. R.

doi:10.1101/2025.11.30.691454

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bioRxiv · 10.1101/2025.11.30.691454

IgG-Bridging-Seeded Synergistic Aggregation of SARS-CoV-2 Spikes Underlies Potent Neutralization by A Low-Affinity Antibody

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Abstract

Mechanistic studies of viral neutralization typically prioritize high-affinity antibodies, relegating low-affinity binders to the sidelines. We report P5-1C8, a Class 1 SARS-CoV-2 antibody that exemplifies this underexplored "low-affinity yet high-potency" phenotype, 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, we show 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. Graphical AbstractLow-affinity antibodies are frequently disregarded in discovery pipelines. This work reports P5-1C8, a Class 1 SARS-CoV-2 antibody with weak trimer binding (KD-to-IC50 > 3,700-fold) yet potent neutralization of Omicron JN.1. Structural, biophysical, functional and coarse-grained simulations collectively demonstrate that transient inter-spike IgG bridging seeds higher-order aggregation, which in turn drives neutralization and provides a mechanistic framework. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/691454v1_ufig1.gif" ALT="Figure 1000"> View larger version (79K): org.highwire.dtl.DTLVardef@1d4f132org.highwire.dtl.DTLVardef@1274400org.highwire.dtl.DTLVardef@e186a6org.highwire.dtl.DTLVardef@4f1870_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Lv, N., Chen, P., Dai, X., Xu, H., Li, Z., Shan, Z., Li, J., Guo, F., Chen, Y., Huang, Y., Dong, G., Jiang, Y., Chen, L., Nan, X., Zhao, H., Zhang, K., Fan, S., Dong, Y., Liu, D., wang, x., Huang, D., Pan, X., Chen, C., Liu, Z., Yan, L.-T., Zhang, Q., Zhang, L., Zhao, Y., Yang, Y. R.. 2025-12-01. IgG-Bridging-Seeded Synergistic Aggregation of SARS-CoV-2 Spikes Underlies Potent Neutralization by A Low-Affinity Antibody. https://doi.org/10.1101/2025.11.30.691454

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