Pan-COVID TherapeuticSevere 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 largepercentage of Americans are not fully vaccinated. About 15% of COVID-19 patients require hospitalization with5% requiring intensive care, among whom nearly half of patients succumb to the disease without an effectivetherapeutic 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 (tensof nM) to warrant therapeutic development. We have generated a high affinity ACE2 (>100-fold). This engineeredACE2 will be effective against all variants, including delta. Fusion of this engineered ACE2 to a humanimmunoglobulin Fc region is expected to result in superior pharmacokinetics, as Fc will confer a long circulatinghalf-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 forneutralization escape mutants, as any mutation that decreases binding to the decoy will reduce binding to thenative receptor, resulting in an attenuated virus. Our engineered ACE2 maintains the peptidase activity thatdecreases angiotensin II (Ang II) concentration to alleviate AGTR1/AGTR2-mediated vasoconstriction thatexacerbates the acute respiratory distress. The active ACE2-Fc will address the underlining pathogenesis ofsevere COVID-19 in addition to blocking the viral entry, and provides superior efficacy versus neutralizingantibodies. During this Phase 1 project, we will engineer an active ACE2 with >100-fold affinity improvement tothe SARS-CoV-2 spike protein, and fuse it to a human Fc. The resulting decoy fusion protein will inhibit viralbinding to its receptor ACE2 as well as locally target the renin-angiotensin system (RAS) to attenuate severerespiratory distress. The outcome of this work will be a novel best-in-class therapy for SARS-CoV-2 andpotentially other viral acute respiratory distress syndromes.
Public Health Relevance Statement: Narrative
Infection by the coronavirus SARS-CoV-2 causes the severe respiratory distress syndrome COVID-19.
Despite the deployment of effective vaccines, the rapid emergence of variants remains a concern. We have
designed a therapeutic protein to prevent viral infection of cells and simultaneously deliver a robust inhibitor of
RAS-mediated lung damage. Because this protein acts as a decoy receptor for viral entry, it will not subject the
virus to selection for escape variants.
Project Terms:
