Pan-COVID Therapeutic

泛COVID治疗 摘要 严重的COVID-19仍然是未接种疫苗人群的迫切未满足的临床需求，特别是SARS- CoV-2 delta和omicron变体在全球范围内传播。尽管迅速部署了有效的疫苗， 美国人没有完全接种疫苗。约15%的COVID-19患者需要住院治疗， 5%需要重症监护，其中近一半的患者死于疾病，没有有效的治疗。 治疗选择由于血管紧张素转换酶2（ACE 2）是SARS病毒的细胞表面受体， CoV-2刺突（S）糖蛋白，用于细胞进入，可溶性ACE 2已被用作诱饵受体，以抑制SARS。 CoV-2感染在体外和体内。然而，野生型人ACE 2的亲和力不够高（数十 的nM）以保证治疗开发。我们已经产生了高亲和力ACE 2（>100倍）。这个工程 ACE 2将对所有变体有效，包括delta。将这种工程化ACE 2融合到人类 预计免疫球蛋白Fc区将产生上级药代动力学，因为Fc将赋予长循环 半衰期和递送至气道粘膜表面（SARS-CoV-2感染的主要部位）的能力。 与抗SARS-CoV-2抗体不同，ACE 2-Fc诱饵融合蛋白将不使病毒经受选择， 中和逃逸突变体，因为任何减少与诱饵结合的突变都会减少与诱饵的结合。 天然受体，导致减毒病毒。我们的工程ACE 2保持肽酶活性， 降低血管紧张素II（Ang II）浓度以减轻AGTR 1/AGTR 2介导的血管收缩， 加重了急性呼吸窘迫活性ACE 2-Fc将解决以下发病机制： 严重的COVID-19除了阻断病毒进入，并提供优于中和的上级疗效 抗体的在这个第一阶段的项目中，我们将设计一个活性ACE 2，其亲和力提高>100倍， SARS-CoV-2刺突蛋白，并将其与人Fc融合。所得到的诱饵融合蛋白将抑制病毒 结合其受体ACE 2，并局部靶向肾素-血管紧张素系统（RAS），以减轻严重的 呼吸窘迫这项工作的结果将是一种新型的SARS-CoV-2最佳疗法， 潜在的其他病毒性急性呼吸窘迫综合征。

Pan-COVID Therapeutic Abstract Severe COVID-19 remains as an urgent unmet clinical need for unvaccinated people, particularly as the SARS- CoV-2 delta and omicron variants spread globally. Despite the rapid deployment of effective vaccines, a large percentage of Americans are not fully vaccinated. About 15% of COVID-19 patients require hospitalization with 5% requiring intensive care, among whom nearly half of patients succumb to the disease without an effective therapeutic option. Because angiotensin-converting enzyme 2 (ACE2) is the cell surface receptor of the SARS- CoV-2 spike (S) glycoprotein for cell entry, soluble ACE2 has been used as a decoy receptor to inhibit SARS- CoV-2 infection in vitro and in vivo. However, the affinity of the wild type human ACE2 is not high enough (tens of nM) to warrant therapeutic development. We have generated a high affinity ACE2 (>100-fold). This engineered ACE2 will be effective against all variants, including delta. Fusion of this engineered ACE2 to a human immunoglobulin Fc region is expected to result in superior pharmacokinetics, as Fc will confer a long circulating half-life and the ability to be delivered to airway mucosal surfaces, the primary site of SARS-CoV-2 infection. Unlike anti-SARS-CoV-2 antibodies, the ACE2-Fc decoy fusion protein will not subject the virus to selection for neutralization escape mutants, as any mutation that decreases binding to the decoy will reduce binding to the native receptor, resulting in an attenuated virus. Our engineered ACE2 maintains the peptidase activity that decreases angiotensin II (Ang II) concentration to alleviate AGTR1/AGTR2-mediated vasoconstriction that exacerbates the acute respiratory distress. The active ACE2-Fc will address the underlining pathogenesis of severe COVID-19 in addition to blocking the viral entry, and provides superior efficacy versus neutralizing antibodies. During this Phase 1 project, we will engineer an active ACE2 with >100-fold affinity improvement to the SARS-CoV-2 spike protein, and fuse it to a human Fc. The resulting decoy fusion protein will inhibit viral binding to its receptor ACE2 as well as locally target the renin–angiotensin system (RAS) to attenuate severe respiratory distress. The outcome of this work will be a novel best-in-class therapy for SARS-CoV-2 and potentially other viral acute respiratory distress syndromes.