A novel biparatopic hybrid antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy

Abstract

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain of the viral Spike (S) glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain of S. This molecule shows exceptional performance in vitro , inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic viral infection in a standard 96-h co-incubation assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.

COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection

“…As an alternative, a strategy to enhance mAb potential is the biparatopic therapy, the 89C8-ACE2 [ 143 ], which combines a monoclonal antibody (89C8) that recognizes the N-terminal domain (NTD) of the S protein, and the ectodomain of ACE2, which binds to the RBD. This approach showed potent neutralizing activity in pseudovirus and live virus assays.…”

Neutralizing antibodies targeting SARS-CoV-2 spike protein

“…The engineered molecule shows potent inhibition to both S-pseudovirus and authentic virus, while the IC 50 to pseudotyped virus is below 100 pM, about 100-fold more potent than ACE2-Fc itself. The special class of hybrid antibody-receptor design may offer the potential to treat COVID-19 ( Miao et al, 2020 ). Interestingly, researchers from Regeneron Pharmaceuticals screened fully human antibodies from 3 SARS-CoV-2 convalescent patients and their humanized mice model, and identified pairs of highly-potent individual antibodies that simultaneously bind the RBD of spike protein.…”

Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy

“…Other studies have attempted to increase the valency of ACE2 or ACE2 mutants by linking them to a trimerization domain instead of an IgG1 Fc to generate mutant ACE2 trimers, demonstrating, in some cases, better potency than ACE2-Fc dimers [ 143 , 144 ]. Another approach linked an NTD binding mAb to ACE2-Fc, resulting in ~100 fold improvement over ACE2-Fc in binding and neutralization [ 145 ].…”