Wang Yanqun, Yan An, Song Deyong, Dong Chuangchuang, Rao Muding, Gao Yuanzhu, Qi Ruxi, Ma Xiaomin, Wang Qiaoping, Xu Hongguang, Liu Hong, Han Jing, Duan Maoqin, Liu Shuo, Yu Xiaoping, Zong Mengqi, Feng Jianxia, Jiao Jie, Zhang Huimin, Li Min, Yu Beibei, Wang Yanxia, Meng Fanhao, Ni Xiaodan, Li Ying, Shen Zhenduo, Sun Baiping, Shao Xin, Zhao Haifeng, Zhao Yanyan, Li Rui, Zhang Yanan, Du Guangying, Lu Jun, You Chunna, Jiang Hua, Zhang Lu, Wang Lan, Dou Changlin, Liu Zheng, Zhao Jincun
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Cell Discov. 2023 Jan 7;9(1):3. doi: 10.1038/s41421-022-00509-9.
SARS-CoV-2 Omicron subvariants have demonstrated extensive evasion from monoclonal antibodies (mAbs) developed for clinical use, which raises an urgent need to develop new broad-spectrum mAbs. Here, we report the isolation and analysis of two anti-RBD neutralizing antibodies BA7208 and BA7125 from mice engineered to produce human antibodies. While BA7125 showed broadly neutralizing activity against all variants except the Omicron sublineages, BA7208 was potently neutralizing against all tested SARS-CoV-2 variants (including Omicron BA.1-BA.5) except Mu. By combining BA7208 and BA7125 through the knobs-into-holes technology, we generated a biparatopic antibody BA7208/7125 that was able to neutralize all tested circulating SARS-CoV-2 variants. Cryo-electron microscopy structure of these broad-spectrum antibodies in complex with trimeric Delta and Omicron spike indicated that the contact residues are highly conserved and had minimal interactions with mutational residues in RBD of current variants. In addition, we showed that administration of BA7208/7125 via the intraperitoneal, intranasal, or aerosol inhalation route showed potent therapeutic efficacy against Omicron BA.1 and BA.2 in hACE2-transgenic and wild-type mice and, separately, effective prophylaxis. BA7208/7125 thus has the potential to be an effective candidate as an intervention against COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）奥密克戎亚型毒株已显示出对为临床使用而开发的单克隆抗体（mAbs）具有广泛的逃逸能力，这迫切需要开发新的广谱单克隆抗体。在此，我们报告了从经过工程改造以产生人抗体的小鼠中分离和分析两种抗受体结合域（RBD）中和抗体BA7208和BA7125的情况。虽然BA7125对除奥密克戎亚谱系外的所有变体均表现出广泛的中和活性，但BA7208对除缪毒株外的所有测试的SARS-CoV-2变体（包括奥密克戎BA.1-BA.5）均具有强效中和作用。通过旋钮入孔技术将BA7208和BA7125结合，我们产生了一种双特异性抗体BA7208/7125，它能够中和所有测试的循环SARS-CoV-2变体。这些广谱抗体与三聚体德尔塔和奥密克戎刺突蛋白复合物的冷冻电子显微镜结构表明，接触残基高度保守，并且与当前变体RBD中的突变残基相互作用最小。此外，我们表明，通过腹腔内、鼻内或气溶胶吸入途径给予BA7208/7125对hACE2转基因小鼠和野生型小鼠中的奥密克戎BA.1和BA.2显示出强效治疗效果，并且分别具有有效的预防作用。因此，BA7208/7125有可能成为对抗2019冠状病毒病（COVID-19）的有效候选药物。
