Multimodal reasoning for broadly neutralizing antibody discovery from label-free human B cell repertoires across virus families

Abstract:Discovering broadly neutralizing antibodies (bnAbs) from human natural immune repertoires remains a fundamental challenge in immunology, hindered by: the extreme rarity of bnAb, incomplete understanding of their cellular origins across pathogens, and the inability of existing computational tools to generalize across emerging viral threats. Here we present ImmuneAgent, a closed-loop AI system that integrates multimodal reasoning with continual meta-learning and wet-lab feedback to overcome these barriers. Applied to screen the natural BCR repertoires from vaccinated or infected cohorts, the system achieves a ~55% neutralization antibody discovery rate (60 of 110 cloned candidates) and a ~11% bnAb yield (12 of 110), substantially outperforming a state-of-the-art sequence-based neutralization predictor or cofolding models evaluated at the same cloning budget. Five ImmuneAgent-discovered antibodies conferred 100% in vivo protection against lethal influenza challenge, comparable to the clinical-stage therapeutic MEDI8852. The system recovered the cellular and structural determinants of bnAb activity and identified FCRL5+CD27+ atypical memory B cells as a conserved bnAb reservoir and hydrophobic interface enrichment as a cross-viral structural signature, which generalized to unseen antigens, discovering human metapneumovirus (hMPV) cross-neutralizing and human papillomavirus (HPV)-neutralizing antibodies without antigen-specific sorting. These results validate that ImmuneAgent is a generalizable framework for rapid therapeutic antibody discovery against emerging viral threats.

Quantitative Methods (q-bio.QM); Artificial Intelligence (cs.AI); Computational Engineering, Finance, and Science (cs.CE); Cell Behavior (q-bio.CB)

arXiv:2610.03160 [q-bio.QM]

(or arXiv:2610.03160v1 [q-bio.QM] for this version)

https://doi.org/10.48550/arXiv.2610.03160 Focus to learn more arXiv-issued DOI via DataCite (pending registration)

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