Pan-COVID Therapeutic Abstract Severe COVID-19

Project Summary/Abstract: 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 (rt100-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 rt100-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.