Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617.
Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617.
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单特异性和双特异性单克隆 SARS-CoV-2 中和抗体，保持针对 B.1.617 的效力。
DOI：
10.1101/2021.12.21.473733
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发表时间：
2021
期刊：
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作者：
Peng,Lei;Hu,Yingxia;Mankowski,MadeleineC;Ren,Ping;Chen,RitaE;Wei,Jin;Zhao,Min;Li,Tongqing;Tripler,Therese;Ye,Lupeng;Chow,RyanD;Fang,Zhenhao;Wu,Chunxiang;Dong,MatthewB;Cook,Matthew;Wang,Guilin;Clark,Paul;Nelson,Bryce;
到目前为止，新冠肺炎病原体SARS-CoV-2已感染数亿人，导致500多万人死亡。尽管有多种疫苗可用，但突破性感染尤其是通过新出现的变种发生。有效的治疗选择，如单抗(MAbbs)仍然至关重要。在这里，我们报告了有效中和SARS-CoV-2变异株的单抗的发展、冷冻-EM结构和功能分析。通过高通量的单细胞测序，我们鉴定了两个高强度的SARS-CoV-2中和单抗克隆，它们具有个位数的纳摩尔亲和力和低的皮摩尔亲和力，并产生了双特异性抗体。铅抗体对历史上的SARS-CoV-2和几个新出现的令人担忧的变种显示出很强的抑制活性。我们解决了几个冷冻-EM结构，在~3 á分辨率这些中和抗体与灌流尖峰三聚体胞外区的复合体，并揭示了不同的表位，结合模式和构象。这些铅克隆在体内也显示出在预防和治疗环境中对真正的SARS-CoV-2的有效效果。我们还产生了人源化抗体并对其进行了鉴定，以促进翻译和药物开发。人源化克隆对原始病毒和B.1.617.2 Delta变异株都有很强的效力。这些单抗扩大了针对SARS-CoV-2和新出现的变种的治疗方法。
COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identify two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generate a bispecific antibody. Lead antibodies show strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solve several cryo-EM structures at ~3 Å resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and reveal distinct epitopes, binding patterns, and conformations. The lead clones also show potent efficacy in vivo against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generate and characterize a humanized antibody to facilitate translation and drug development. The humanized clone also has strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.