ACE2-like Catalytic Activity in Anti-SARS-CoV-2 Spike Protein Monoclonal Antibodies

Many people are affected by difficult-to-understand clinical phenomena associated with acute SARS-CoV-2 infection and by post-acute sequelae of COVID-19 (PASC, or long COVID, LC). The mechanisms responsible for the clinical phenomena have not been well established. The host cell receptor for SARS-CoV-2 is human angiotensin-converting enzyme 2 (ACE2), which binds the SARS-CoV-2 spike protein receptor-binding domain (RBD) to initiate infection. We hypothesized that some people may produce anti-RBD antibodies that sufficiently resemble ACE2 structure to have ACE2-like catalytic activity after infection, and such antibodies are hypothesized to contribute to disease pathogenesis. Our previous studies showed that ACE2-like catalytic activity was associated with immunoglobulin in some acute and convalescent COVID-19 patients. ACE2-like catalytic activity correlated with blood pressure changes following a moderate exercise challenge in people convalescing from COVID-19. To further establish that ACE2-like catalytic activity could be attributed to antibodies, we screened human monoclonal antibodies (mAbs) against SARS-CoV-2 spike protein from three different research centers and others purchased from a commercial source for ACE2-like catalytic activity. We identified four human monoclonal antibodies with ACE2-like catalytic activity. The ACE2-like catalytic activity of these mAbs was not inhibited by MLN-4760, a compound that inhibits native human ACE2 catalytic activity, nor by EDTA, unlike native ACE2, a zinc metalloprotease, but was inhibited by an overlapping pool of spike peptides. Enzyme kinetic studies showed that the mAbs had substantially lower Vmax and Km values than native ACE2, consistent with the characteristics of other catalytic antibodies. The data therefore suggested that the antibodies cleave ACE2 substrate via a mechanism different from native ACE2. The identification of specific mAbs with ACE2-like catalytic activity supports the hypothesis that antibodies induced by SARS-CoV-2 infection could help mediate the pathogenesis of COVID-19 and LC, and, more generally, the hypothesis that catalytic antibodies induced by infectious agents can contribute to disease pathogenesis.