Effective therapies are urgently needed for the SARS-CoV-2/COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. A high-affinity Fab was selected from one of the libraries and converted to a full-size antibody, IgG1 ab1, which competed with human ACE2 for binding to RBD. It potently neutralized replication-competent SARS-CoV-2 but not SARS-CoV, as measured by two different tissue culture assays, as well as a replication-competent mouse ACE2-adapted SARS-CoV-2 in BALB/c mice and native virus in hACE2-expressing transgenic mice showing activity at the lowest tested dose of 2 mg/kg. IgG1 ab1 also exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection. The mechanism of neutralization is by competition with ACE2 but could involve antibody-dependent cellular cytotoxicity (ADCC) as IgG1 ab1 had ADCC activity in vitro. The ab1 sequence has a relatively low number of somatic mutations, indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 did not aggregate, did not exhibit other developability liabilities, and did not bind to any of the 5,300 human membrane-associated proteins tested. These results suggest that IgG1 ab1 has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 d of availability of antigen for panning) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.

SARS-CoV-2/COVID-19 大流行迫切需要有效的治疗方法。我们通过针对 SARS-CoV-2 刺突 (S) 糖蛋白的受体结合域 (RBD) 进行淘选，从大型噬菌体展示的 Fab、scFv 和 VH 文库中鉴定出全人单克隆抗体 (mAb) 组。从其中一个文库中选择了高亲和力 Fab，并将其转化为全尺寸抗体 IgG1 ab1，它与人 ACE2 竞争与 RBD 的结合。通过两种不同的组织培养测定以及 BALB/c 小鼠和天然病毒中具有复制能力的小鼠 ACE2 适应的 SARS-CoV-2 测量，它有效中和了具有复制能力的 SARS-CoV-2，但不能中和 SARS-CoV在表达 hACE2 的转基因小鼠中，在最低测试剂量 2 mg/kg 下显示出活性。 IgG1 ab1 在 SARS-CoV-2 感染的仓鼠模型中也表现出较高的预防和治疗功效。中和机制是通过与 ACE2 竞争，但可能涉及抗体依赖性细胞毒性 (ADCC)，因为 IgG1 ab1 在体外具有 ADCC 活性。 ab1 序列的体细胞突变数量相对较少，表明在自然 SARS-CoV-2 感染期间或通过基于 RBD 的疫苗可以快速引发 ab1 样抗体。 IgG1 ab1 没有聚集，没有表现出其他可开发性缺陷，并且没有与测试的 5,300 种人膜相关蛋白中的任何一种结合。这些结果表明 IgG1 ab1 具有治疗和预防 SARS-CoV-2 感染的潜力。强效单克隆抗体的快速鉴定（在获得用于淘选的抗原后 6 天内）显示了大型抗体库对于应对新兴微生物的公共健康威胁的价值。