CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Nat Immunol. 2022 Mar;23(3):423-430. doi: 10.1038/s41590-022-01138-w. Epub 2022 Feb 28.
The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.
全球严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）大流行需要针对 2019 年冠状病毒病（COVID-19）的有效疗法，而中和抗体是一种很有前途的疗法。先前已经描述了一对非竞争性的人源中和抗体（B38 和 H4），可阻断 SARS-CoV-2 与其受体 ACE2 的结合。在这里，我们开发了 bsAb15，这是一种基于 B38 和 H4 的双特异性单克隆抗体（bsAb）。bsAb15 比这些亲本抗体具有更高的中和效率，产生的选择性压力更小，并保留对大多数关注的 SARS-CoV-2 变体的中和能力（对 Delta 变体具有更强的中和活性）。我们还针对这两种亲本 mAb、mAb 鸡尾酒和 bsAb15 的逃逸突变体进行了选择，证明 bsAb15 可以有效地中和所有单 mAb 逃逸突变体。此外，bsAb15 的预防性和治疗性应用降低了感染的非人类灵长类动物和人 ACE2 转基因小鼠中的病毒滴度。因此，这种 bsAb 是治疗和预防严重 COVID-19 的一种可行且有效的策略。
