Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC₅₀ < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.

抗体对于抵抗 SARS-CoV-2 的免疫保护至关重要，其中一些抗体可紧急用作治疗药物。在这里，我们鉴定了 377 种识别病毒刺突的人类单克隆抗体 (mAb)，并主要关注与受体结合域 (RBD) 结合的 80 种。我们设计了一种竞争数据驱动的方法来绘制 RBD 结合位点。我们发现，虽然抗体结合位点广泛分散，但中和抗体结合是集中的，几乎所有高抑制性单克隆抗体 (IC ₅₀ < 0.1 μg/mL) 都会阻断受体相互作用，除了结合 N 端结构域中独特表位的单克隆抗体外。许多中和单克隆抗体使用公共 V 基因并且接近种系。我们通过 19 个 Fab 抗原结构的 X 射线晶体学和冷冻电子显微镜剖析了这一大组抗体的识别结构基础。我们发现了一些强效抑制性抗体的新结合模式，并证明强中和性单克隆抗体在动物模型中具有预防性或治疗性保护作用。