Li Wenping, Wang Fulian, Li Yu, Yan Lei, Liu Lili, Zhu Wei, Ma Peixiang, Shi Xiaojie, Yang Guang
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Vaccines (Basel). 2023 Mar 31;11(4):771. doi: 10.3390/vaccines11040771.
The majority of neutralizing antibodies (NAbs) against SARS-CoV-2 recognize the receptor-binding domain (RBD) of the spike (S) protein. As an escaping strategy, the RBD of the virus is highly variable, evolving mutations to thwart a natural immune response or vaccination. Targeting non-RBD regions of the S protein thus provides a viable alternative to generating potential, robust NAbs. Using a pre-pandemic combinatorial antibody library of 10, through an alternate negative and positive screening strategy, 11 non-RBD-targeting antibodies are identified. Amongst one NAb that binds specifically to the N-terminal domain of the S protein, SA3, shows mutually non-exclusive binding of the angiotensin-converting enzyme 2 receptor with the S protein. SA3 appears to be insensitive to the conformational change and to interact with both the "open" and "closed" configurations of the trimeric S protein. SA3 shows compatible neutralization as S-E6, an RBD-targeting NAb, against the wild type and variant of concern (VOC) B.1.351 (Beta) of the SARS-CoV-2 pseudo virus. More importantly, the combination of SA3 with S-E6 is synergistic and recovers from the 10-fold loss in neutralization efficacy against the VOC B.1.351 pseudo virus.
大多数针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的中和抗体（NAbs）识别刺突（S）蛋白的受体结合域（RBD）。作为一种逃逸策略，该病毒的RBD高度可变，会发生突变以阻碍自然免疫反应或疫苗接种。因此，靶向S蛋白的非RBD区域为产生潜在的强效NAbs提供了一种可行的替代方案。利用一个大流行前包含10种抗体的组合抗体文库，通过交替的阴性和阳性筛选策略，鉴定出11种靶向非RBD的抗体。在一种与S蛋白N端结构域特异性结合的NAb中，SA3显示出血管紧张素转换酶2受体与S蛋白相互非排他性结合。SA3似乎对构象变化不敏感，并与三聚体S蛋白的“开放”和“封闭”构象相互作用。SA3与一种靶向RBD的NAb S-E6一样，对SARS-CoV-2假病毒的野生型和关注变体（VOC）B.1.351（贝塔）具有兼容的中和作用。更重要的是，SA3与S-E6的组合具有协同作用，可弥补针对VOC B.1.351假病毒中和效力10倍的损失。
