Jiang Wen, Zhang Zherui, Zhu Yuhe, Chen Ben, Gu Chunying, Liu Zhiyan, Zhang Xukai, Xiong Hualong, Zhang Yanan, Zheng Bin, Wang Rongjuan, Jiao Shasha, Wang An, Zhang Tianying, Zhang Jinchao, Wang Shuang, Zhang Bo, Li Gang, Gui Xun
Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai, China.
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
Front Pharmacol. 2022 Jul 8;13:926750. doi: 10.3389/fphar.2022.926750. eCollection 2022.
Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, several variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged and have consistently replaced the previous dominant variant. Therapeutics against variants of SARS-CoV-2 are urgently needed. Ideal SARS-CoV-2 therapeutic antibodies would have high potency in viral neutralization against several emerging variants. Neutralization antibodies targeting SARS-CoV-2 could provide immediate protection after SARS-CoV-2 infection, especially for the most vulnerable populations. In this work, we comprehensively characterize the breadth and efficacy of SARS-CoV-2 RBD-targeting fully human monoclonal antibody (mAb) MW3321. MW3321 retains full neutralization activity to all tested 12 variants that have arisen in the human population, which are assigned as VOC (Variants of Concern) and VOI (Variants of Interest) due to their impacts on public health. Escape mutation experiments using replicating SARS-CoV-2 pseudovirus show that escape mutants were not generated until passage 6 for MW3321, which is much more resistant to escape mutation compared with another clinical staged SARS-CoV-2 neutralizing mAb MW3311. MW3321 could effectively reduce viral burden in hACE2-transgenic mice challenged with either wild-type or Delta SARS-CoV-2 strains through viral neutralization and Fc-mediated effector functions. Moreover, MW3321 exhibits a typical hIgG1 pharmacokinetic and safety profile in cynomolgus monkeys. These data support the development of MW3321 as a monotherapy or cocktail against SARS-CoV-2-related diseases.
自2019年冠状病毒病（COVID-19）大流行爆发以来，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）出现了几种变体，并持续取代了先前占主导地位的变体。迫切需要针对SARS-CoV-2变体的治疗方法。理想的SARS-CoV-2治疗性抗体应对几种新出现的变体具有高效的病毒中和能力。靶向SARS-CoV-2的中和抗体可在SARS-CoV-2感染后提供即时保护，尤其是对最脆弱的人群。在这项研究中，我们全面表征了靶向SARS-CoV-2受体结合域（RBD）的全人源单克隆抗体（mAb）MW3321的广度和效力。MW3321对人群中出现的所有12种测试变体均保持完全中和活性，这些变体因其对公共卫生的影响而被指定为关注变体（VOC）和感兴趣变体（VOI）。使用复制型SARS-CoV-2假病毒进行的逃逸突变实验表明，MW3321直到第6代才产生逃逸突变体，与另一种临床阶段的SARS-CoV-2中和mAb MW3311相比，其对逃逸突变的抗性要强得多。MW3321可通过病毒中和作用和Fc介导的效应功能有效降低用野生型或Delta SARS-CoV-2毒株攻击的hACE2转基因小鼠的病毒载量。此外，MW3321在食蟹猴中表现出典型的hIgG1药代动力学和安全性特征。这些数据支持将MW3321开发为针对SARS-CoV-2相关疾病的单一疗法或联合疗法。
