ABSTRACT

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain of the viral Spike (S) glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain of S. This molecule shows exceptional performance in vitro, inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic viral infection in a standard 96-h co-incubation assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.

摘要

在缺乏有效的预防SARS-CoV-2感染的有效疫苗或治疗COVID-19的有效药物的情况下，使用恢复期血清的被动免疫疗法的积极结果提供了强有力的线索。我们已经开发出一类新的四价双截点疗法89C8-ACE2。它结合了单克隆抗体（89C8）的特异性，该抗体可识别病毒Spike（S）糖蛋白相对保守的N末端结构域，以及ACE2的胞外域，该区域与S的受体结合域结合。体外表现抑制重组S1与ACE2的相互作用以及S-假型慢病毒的ACE2过表达的细胞转导，IC50基本上低于100 pM，效力比ACE2-Fc本身高约100倍。此外，在低纳摩尔浓度的标准96小时共温育试验中，89C8-ACE2能够中和真正的病毒感染，使此类分子成为治疗应用的有前途的领先者。