发表机构
Nankai University; Peking Union Medical College, Chinese Academy of Medical Sciences; Institute of Biophysics, Chinese Academy of Sciences; Guangzhou National Laboratory; Tianjin University of Traditional Chinese Medicine; Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College（南开大学; 中国医学科学院北京协和医学院; 中国科学院生物物理研究所; 广州国家实验室; 天津中医药大学; 中国医学科学院北京协和医学院苏州系统医学研究所）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
提出闭环AI系统ImmuneAgent，结合多模态推理与持续元学习，从人类B细胞库中高效发现广泛中和抗体，显著提升发现率并验证跨病毒通用性。
AI 中文摘要
从人类天然免疫库中发现广泛中和抗体（bnAbs）仍是免疫学中的一项基本挑战，其障碍包括：bnAbs的极端稀有性、对其跨病原体细胞起源的不完全理解，以及现有计算工具无法推广至新兴病毒威胁。在此，我们提出ImmuneAgent，一个闭环AI系统，将多模态推理与持续元学习和湿实验反馈相结合，以克服这些障碍。该系统应用于筛选来自疫苗接种或感染队列的天然BCR库，实现了约55%的中和抗体发现率（110个克隆候选中的60个）和约11%的bnAb产率（110个中的12个），显著优于在相同克隆预算下评估的最先进的基于序列的中和预测器或共折叠模型。五个ImmuneAgent发现的抗体在体内对致命性流感挑战提供了100%的保护，与临床阶段治疗药物MEDI8852相当。该系统恢复了bnAb活性的细胞和结构决定因素，并鉴定出FCRL5+CD27+非典型记忆B细胞作为保守的bnAb储存库，以及疏水界面富集作为跨病毒结构特征，该特征可推广至未见抗原，发现了人类偏肺病毒（hMPV）交叉中和抗体和人乳头瘤病毒（HPV）中和抗体，无需抗原特异性分选。这些结果验证了ImmuneAgent作为针对新兴病毒威胁的快速治疗性抗体发现的通用框架。
英文摘要
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.
