TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.

中文翻译：

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一对非竞争性中和人单克隆抗体在 SARS-CoV-2 感染模型中预防疾病

TRIANNI小鼠携带一整套人免疫球蛋白V区基因片段，是快速分离人单克隆抗体的有力工具。在用编码 SARS-CoV-2 刺突蛋白的 DNA 对这些小鼠进行免疫接种并用刺突蛋白进行加强后，我们鉴定出了 29 种与 SARS-CoV-2 刺突蛋白发生反应的杂交瘤抗体。九种抗体可中和 SARS-CoV-2 感染，IC50 值在亚纳摩尔范围内。ELISA 结合研究和 DNA 序列分析揭示了一组由三种克隆相关的中和抗体组成的簇，它们靶向受体结合结构域并与细胞受体 hACE2 竞争。第二簇六种克隆相关的中和抗体与刺突蛋白的N末端结构域结合，而不与 hACE2 或簇 1 抗体的结合竞争。选择对一个簇中的抗体具有抗性的 SARS-CoV-2 突变体仍会被另一簇中的抗体中和。来自这两个簇的抗体显着减少了人类 ACE2 转基因小鼠中的病毒传播，并保护动物免受 SARS-CoV-2 引起的体重减轻。这两簇强效非竞争性 SARS-CoV-2 中和抗体为治疗和预防 COVID-19 提供了潜在的候选药物。该研究进一步支持具有人类免疫球蛋白基因库的转基因动物作为大流行防范举措的强大平台。