ABSTRACT

Effective therapies are urgently needed for COVID-19. Here we describe the identification of a new stable human immunoglobulin G1 heavy-chain variable (VH) domain scaffold that was used for the construction of a large library, lCAT6, of engineered human VHs. This library was panned against the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. Two VH domains (VH ab6 and VH m397) were selected and fused to Fc for increased half-life in circulation. The VH-Fc ab6 and m397 specifically neutralized SARS-CoV-2 with high potencies (50% neutralization at 0.35 µg/ml and 1.5 µg/ml, respectively) as measured by two independent replication-competent virus neutralization assays. Ab6 and m397 competed with ACE2 for binding to RBD, suggesting a competitive mechanism of virus neutralization. These VH domains may have potential applications for prophylaxis and therapy of COVID-19 alone or in combination, as well as for diagnosis and as tools for research.

摘要

COVID-19迫切需要有效的疗法。在这里，我们描述了一种新的稳定的人免疫球蛋白G1重链可变（VH）结构域支架的鉴定，该支架用于构建工程人VH的大型文库lCAT6。针对SARS-CoV-2尖峰（S）糖蛋白的受体结合域（RBD）淘选了该文库。选择了两个VH域（VH ab6和VH m397），并与Fc融合以增加循环半衰期。通过两个独立的具有复制能力的病毒中和测定法，VH-Fc ab6和m397以高效力（分别以0.35 µg / ml和1.5 µg / ml的50％中和）特异性中和SARS-CoV-2。Ab6和m397与ACE2竞争与RBD的结合，表明病毒中和的竞争机制。