Wang Zhihong, Shi Zhuangzhuang, Liao Xiaochen, Quan Guiqi, Dong Hui, Zhao Pinnan, Zhou Yangyihua, Shi Ning, Wang Jie, Wu Yahui, Qiao Chunxia, Li Xin Ying, Zhang Ran, Wang Zekun, Wang Tiecheng, Gao Xiang, Feng Jiannan, Luo Longlong
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, P. R. China.
Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, P. R. China.
Adv Sci (Weinh). 2024 Dec;11(45):e2402975. doi: 10.1002/advs.202402975. Epub 2024 Oct 7.
SARS-CoV-2 Omicron sublineages escape most preclinical/clinical neutralizing antibodies in development, suggesting that previously employed antibody screening strategies are not well suited to counteract the rapid mutation of SARS-CoV-2. Therefore, there is an urgent need to screen better broad-spectrum neutralizing antibody. In this study, a comprehensive approach to design broad-spectrum inhibitors against both SARS-CoV-1 and SARS-CoV-2 by leveraging the structural diversity of nanobodies is proposed. This includes the de novo design of a fully human nanobody library and the camel immunization-based nanobody library, both targeting conserved epitopes, as well as the development of multivalent nanobodies that bind nonoverlapping epitopes. The results show that trivale B11-E8-F3, three nanobodies joined tandemly in trivalent form, have the broadest spectrum and efficient neutralization activity, which spans from SARS-CoV-1 to SARS-CoV-2 variants. It is also demonstrated that B11-E8-F3 has a very prominent preventive and some therapeutic effect in animal models of three authentic viruses. Therefore, B11-E8-F3 has an outstanding advantage in preventing SARS-CoV-1/SARS-CoV-2 infections, especially in immunocompromised populations or elderly people with high-risk comorbidities.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）奥密克戎亚谱系可逃避大多数正在研发的临床前/临床中和抗体，这表明先前采用的抗体筛选策略不太适合应对SARS-CoV-2的快速突变。因此，迫切需要筛选出更好的广谱中和抗体。在本研究中，提出了一种通过利用纳米抗体的结构多样性来设计针对SARS-CoV-1和SARS-CoV-2的广谱抑制剂的综合方法。这包括从头设计一个完全人源的纳米抗体文库和基于骆驼免疫的纳米抗体文库，二者均靶向保守表位，以及开发结合非重叠表位的多价纳米抗体。结果表明，三价的B11-E8-F3（由三个纳米抗体以三价形式串联而成）具有最广的谱和高效的中和活性，其活性范围涵盖从SARS-CoV-1到SARS-CoV-2变体。还证明了B11-E8-F3在三种真实病毒的动物模型中具有非常显著的预防作用和一定的治疗作用。因此，B11-E8-F3在预防SARS-CoV-1/SARS-CoV-2感染方面具有突出优势，尤其是在免疫功能低下人群或患有高危合并症的老年人中。
