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

Hantao Lou; Jianqing Zheng; Can Yue; Meihan Zhang; Yuanchao Bao; Yu Chen; Mengting Huang; Yupeng Yang; Qianyu Pan; Nana Fu; Yansong Shi; Hongli Li; Yangyang Chai; Ruyi Chen; Wansheng Li; Zhu Liang; Rongmei Yao; Yuanhan Mo; Lei Wang; Chunmei Wang; Yun Quan; Qiong Zhang; Xiangxi Wang; Xuetao Cao

arXiv · 2610.03160

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

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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.

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Hantao Lou, Jianqing Zheng, Can Yue, Meihan Zhang, Yuanchao Bao, Yu Chen, Mengting Huang, Yupeng Yang, Qianyu Pan, Nana Fu, Yansong Shi, Hongli Li, Yangyang Chai, Ruyi Chen, Wansheng Li, Zhu Liang, Rongmei Yao, Yuanhan Mo, Lei Wang, Chunmei Wang, Yun Quan, Qiong Zhang, Xiangxi Wang, Xuetao Cao. 2026-10-02. Multimodal reasoning for broadly neutralizing antibody discovery from label-free human B cell repertoires across virus families. https://arxiv.org/abs/2610.03160

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