Hanke Leo, Das Hrishikesh, Sheward Daniel J, Perez Vidakovics Laura, Urgard Egon, Moliner-Morro Ainhoa, Kim Changil, Karl Vivien, Pankow Alec, Smith Natalie L, Porebski Bartlomiej, Fernandez-Capetillo Oscar, Sezgin Erdinc, Pedersen Gabriel K, Coquet Jonathan M, Hällberg B Martin, Murrell Ben, McInerney Gerald M
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Nat Commun. 2022 Jan 10;13(1):155. doi: 10.1038/s41467-021-27610-z.
Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer-dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.
与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白结合的抗体具有治疗潜力，但新出现的变体显示出病毒逃逸的可能性。这凸显了对具有独特和新颖中和机制的治疗分子的需求。在这里，我们描述了一种纳米抗体的分离，该纳米抗体同时与来自SARS-CoV-2不同刺突三聚体的两个受体结合域（RBD）相互作用，迅速诱导刺突三聚体二聚体的形成，导致其失去与宿主细胞受体血管紧张素转换酶2（ACE2）结合的能力。我们表明，这种纳米抗体能有效中和SARS-CoV-2，包括β和δ变体，并能交叉中和SARS-CoV。此外，我们在人ACE2转基因小鼠模型中证明了该纳米抗体对SARS-CoV-2和β变体的治疗潜力。这种天然产生的双特异性单体纳米抗体为有效灭活病毒抗原建立了一种不同寻常的策略，代表了一种有前景的抗新出现的SARS-CoV-2变体的抗病毒药物。
