Department of Critical Medicine, School of Medicine, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
J Med Virol. 2024 Mar;96(3):e29528. doi: 10.1002/jmv.29528.
The emerging Omicron subvariants have a remarkable ability to spread and escape nearly all current monoclonal antibody (mAb) treatments. Although the virulence of SARS-CoV-2 has now diminished, it remains a significant threat to public health due to its high transmissibility and susceptibility to mutation. Therefore, it is urgent to develop broad-acting and potent therapeutics targeting current and emerging Omicron variants. Here, we identified a panel of Omicron BA.1 spike receptor-binding domain (RBD)-targeted nanobodies (Nbs) from a naive alpaca VHH library. This panel of Nbs exhibited high binding affinity to the spike RBD of wild-type, Alpha B.1.1.7, Beta B.1.351, Delta plus, Omicron BA.1, and BA.2. Through multivalent Nb construction, we obtained a subpanel of ultrapotent neutralizing Nbs against Omicron BA.1, BA.2, BF.7 and even emerging XBB.1.5, and XBB.1.16 pseudoviruses. Protein structure prediction and docking analysis showed that Nb trimer 2F2E5 targets two independent RBD epitopes, thus minimizing viral escape. Taken together, we obtained a panel of broad and ultrapotent neutralizing Nbs against Omicron BA.1, Omicron BA.2, BF.7, XBB.1.5, and XBB.1.16. These multivalent Nbs hold great promise for the treatment against SARS-CoV-2 infection and could possess a superwide neutralizing breadth against novel omicron mutants or recombinants.
新兴的奥密克戎亚变体具有显著的传播和逃逸能力，几乎可以逃避所有当前的单克隆抗体 (mAb) 治疗。尽管 SARS-CoV-2 的毒力现已减弱，但由于其高传染性和易突变性，它仍然对公共健康构成重大威胁。因此，迫切需要开发针对当前和新兴奥密克戎变体的广谱有效治疗方法。在这里，我们从一个原始的羊驼 VHH 文库中鉴定出了一组针对奥密克戎 BA.1 刺突受体结合域 (RBD) 的纳米抗体 (Nb)。该组 Nb 对野生型、Alpha B.1.1.7、Beta B.1.351、Delta plus、Omicron BA.1 和 BA.2 的刺突 RBD 表现出高结合亲和力。通过多价 Nb 构建，我们获得了针对奥密克戎 BA.1、BA.2、BF.7 甚至新兴 XBB.1.5 和 XBB.1.16 假病毒的超效中和 Nb 的亚组。蛋白质结构预测和对接分析表明，Nb 三聚体 2F2E5 靶向两个独立的 RBD 表位，从而最大限度地减少病毒逃逸。总之，我们获得了一组针对奥密克戎 BA.1、奥密克戎 BA.2、BF.7、XBB.1.5 和 XBB.1.16 的广谱和超效中和 Nb。这些多价 Nb 有望成为治疗 SARS-CoV-2 感染的方法，并且可能对新型奥密克戎突变体或重组体具有超宽的中和广度。
