Researchers from Rockefeller and Stanford Universities have developed human monoclonal antibodies that bind to ACE2 on host cells, providing an alternative therapeutic pathway for Covid-19 antibody development. The team immunized humanized mice models with ACE2 extracellular domains and isolated hybrid B cells or hybridomas that produced chimeric antibodies consisting of human Fab domains and a murine Fc domain. Ten candidates were selected that secreted antibodies that impeded SARS-CoV-2 pseudotype infection, and six of the ten chimeric human-mouse antibodies were chosen to be adapted to a human IgG expression for their genetic diversity and binding capacity. All six generated human antibodies blocked a pseudotype SARS-CoV-2 wildtype virus from infecting target cells. The researchers found that the antibodies also inhibited a SARS-CoV-1 pseudovirus, as well as two pangolin and two bat viruses with similar potencies.
The ACE2 site on human cells has natural functions and it is crucial the introduction of antibodies does not impact these functions. With the aid of cryo-electron microscopy, the team found that antibody interactions mimicked favorable binding between SARS-CoV-2 receptor-binding domains and an N-terminal helix of ACE2, a critical juncture for SARS-CoV-2 infection. This molar mimicry enables high binding affinity despite a smaller binding epitope than the virus. In animal models, the anti-ACE2 antibodies were successful as a prophylactic for SARS-CoV-2 infection. Pre-treatment with the anti-ACE2 antibody reduced lung virus replication to near undetectable levels as compared to the control, although the study was conducted against the wild-type virus, and not the variants.
This is a promising new approach to antibody development, though some concerns must be addressed. Firstly, can a high enough concentration of these antibodies be delivered to block enough receptors to be effective against the invading pathogen? Secondly, would blocked receptors interfere with normal cellular physiology? Until extensive human studies are conducted, we cannot know the answer. Given the genetic and structural flexibility of the coronavirus family, it is possible that variants of SARS-CoV-2 may evolve to use other receptor-binding domain epitopes. Nonetheless, this approach is interesting and promising. Another approach is the use of broadly neutralizing monoclonal antibodies targeting conserved epitopes on the spike protein, a number of which have been discovered and some of which are in clinical development. These strategies may be complementary, and antibody cocktails that include ACE2 binding antibodies may be part of the answer following phase one safety and phase two efficacy trials.