Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Rutgers Institute for Translational Medicine and Science, New Brunswick, New Jersey, United States of America.
PLoS One. 2022 Jul 11;17(7):e0271066. doi: 10.1371/journal.pone.0271066. eCollection 2022.
As ACE2 is the critical SARS-CoV-2 receptor, we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung, and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here, after demonstrating in vitro neutralization of SARS-CoV-2 by APN01, and after obtaining preliminary evidence of its tolerability and preventive efficacy in a mouse model, we pursued development of an aerosol formulation. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers has now been initiated (NCT05065645), with subsequent Phase II testing planned for individuals with SARS-CoV-2 infection.
由于 ACE2 是 SARS-CoV-2 的关键受体，我们假设将临床级可溶性人重组 ACE2（APN01）气溶胶给药将在气道中中和 SARS-CoV-2，限制感染在肺部的传播，并减轻肾素-血管紧张素（RAS）和激肽途径中信号失调引起的肺损伤。在这里，在证明 APN01 在体外中和 SARS-CoV-2 之后，并且在小鼠模型中获得了其耐受性和预防功效的初步证据后，我们继续开发气溶胶制剂。作为临床试验的前提，我们评估了气溶胶化后病毒结合活性和血管紧张素 II 切割的酶活性。我们报告了 APN01 的成功气溶胶化，保留了病毒结合以及催化 RAS 活性。在狗中进行了剂量范围发现和 IND 使能重复剂量气溶胶毒理学测试。在最大可行浓度下每天两次进行两周的气溶胶给药未显示出明显的毒性。基于这些结果，一项针对健康志愿者的 I 期临床试验现已启动（NCT05065645），随后计划对 SARS-CoV-2 感染个体进行 II 期测试。
