New Drug Discovery and Development, Biotheus Inc , Zhuhai, China.
The Fifth Affiliated Hospital, Sun Yat-Sen University , Zhuhai, China.
MAbs. 2020 Jan-Dec;12(1):1804241. doi: 10.1080/19420862.2020.1804241.
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 , 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.
在缺乏可有效预防 SARS-CoV-2 感染的疫苗，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阳性结果提供了一个强有力的线索。我们开发了一种新型的四价、双价治疗药物 89C8-ACE2。它结合了一种单克隆抗体（89C8）的特异性，该抗体识别病毒 Spike（S）糖蛋白相对保守的 N 端结构域和 ACE2 的胞外结构域，后者结合 S 的受体结合域。该分子表现出卓越的性能，抑制了重组 S1 与 ACE2 的相互作用，以及 S-假型慢病毒转导 ACE2 过表达细胞，IC50 值远低于 100 pM，效力约比 ACE2-Fc 本身高 100 倍。此外，89C8-ACE2 能够在标准的 96 小时共孵育试验中以低纳摩尔浓度中和真实的病毒感染，使这类分子成为治疗应用的有前途的先导物。
