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 K_m 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.