Jian Fanchong, Wec Anna Z, Feng Leilei, Yu Yuanling, Wang Lei, Wang Peng, Yu Lingling, Wang Jing, Hou Jacob, Berrueta Daniela Montes, Lee Diana, Speidel Tessa, Ma LingZhi, Kim Thu, Yisimayi Ayijiang, Song Weiliang, Wang Jing, Liu Lu, Yang Sijie, Niu Xiao, Xiao Tianhe, An Ran, Wang Yao, Shao Fei, Wang Youchun, Pecetta Simone, Wang Xiangxi, Walker Laura M, Cao Yunlong
Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, China.
Changping Laboratory, Beijing, China.
Nat Microbiol. 2025 Jun 10. doi: 10.1038/s41564-025-02030-7.
Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 receptor-binding domain are used to treat and prevent COVID-19. However, the rapid evolution of SARS-CoV-2 drives continuous escape from therapeutic mAbs. Therefore, the ability to identify broadly neutralizing antibodies (bnAbs) to future variants is needed. Here we use deep mutational scanning to predict viral receptor-binding domain evolution and to select for mAbs neutralizing both existing and prospective variants. A retrospective analysis of 1,103 SARS-CoV-2 wild-type-elicited mAbs shows that this method can increase the probability of identifying effective bnAbs to the XBB.1.5 strain from 1% to 40% in an early pandemic set-up. Among these bnAbs, BD55-1205 showed potent activity to all tested variants. Cryogenic electron microscopy structural analyses revealed the receptor mimicry of BD55-1205, explaining its broad reactivity. Delivery of mRNA-lipid nanoparticles encoding BD55-1205-IgG in mice resulted in serum half-maximal neutralizing antibody titre values of ~5,000 to XBB.1.5, HK.3.1 and JN.1 variants. Combining bnAb identification using viral evolution prediction with the versatility of mRNA delivery technology can enable rapid development of next-generation antibody-based countermeasures against SARS-CoV-2 and potentially other pathogens with pandemic potential.
靶向严重急性呼吸综合征冠状病毒2（SARS-CoV-2）受体结合域的单克隆抗体（mAb）用于治疗和预防2019冠状病毒病（COVID-19）。然而，SARS-CoV-2的快速进化导致其不断逃避治疗性单克隆抗体。因此，需要具备识别针对未来变异株的广泛中和抗体（bnAb）的能力。在此，我们利用深度突变扫描来预测病毒受体结合域的进化，并筛选出能够中和现有及潜在变异株的单克隆抗体。对1103种由SARS-CoV-2野生型诱导产生的单克隆抗体进行的回顾性分析表明，在疫情早期阶段，该方法可将识别针对XBB.1.5毒株的有效广泛中和抗体的概率从1%提高到40%。在这些广泛中和抗体中，BD55-1205对所有测试变异株均表现出强效活性。低温电子显微镜结构分析揭示了BD55-1205的受体模拟特性，解释了其广泛的反应性。在小鼠体内递送编码BD55-1205-IgG的mRNA-脂质纳米颗粒，针对XBB.1.5、HK.3.1和JN.1变异株产生的血清中和抗体半数最大滴度值约为5000。将利用病毒进化预测进行广泛中和抗体识别与mRNA递送技术的多功能性相结合，能够快速开发出针对SARS-CoV-2以及可能具有大流行潜力的其他病原体的下一代基于抗体的应对措施。
