Soluble receptor as a new approach to therapy for COVID-19
The idea of using a soluble viral receptor as a therapeutic inhibitor of virus replication was first developed for HIV in the form of soluble CD4. We have adapted that concept to SARS-CoV-2 by producing a recombinant soluble ACE2 which we term an “ACE2 microbody”. The protein has the ectodomain of ACE2 fused to immunoglobulin heavy chain Fc domain 3. Immunoglobulin Fc is the carboxy-terminal domain of antibodies that holds two antibody chains together and is bound by the Fc receptor on macrophages to arm them for the recognition of pathogens. The protein contains only a single domain of Fc and is termed a microbody because of the shortened Fc. The Fc domain serves to disulphide bond two ACE2 domains together and to increase the half-life of the protein in vivo. The disulfide-bonded ACE2 microbody protein inhibits entry of SARS-CoV-2 spike protein pseudotyped virus and blocks the replication of live SARS-CoV-2 in vitro and in a mouse model. Its potency is 10-fold higher than soluble ACE2 and it can act after virus bound to the cell. The microbody inhibits the entry of other b coronaviruses. The advantages of the approach compared to anti-spike protein monoclonal antibodies are that the virus cannot easily escape by mutating the spike protein gene as the virus has to maintain its affinity for the ACE2 receptor and because both components of the microbody protein are of human origin, the immune system is tolerized to them and will not generate antibodies against the microbody protein. The ability of the ACE2 microbody to block several beta coronaviruses suggest that this protein could be a valuable therapeutic against future SARS-CoV-2 variants and against future coronaviruses that may enter the human population.