Human Anti-Ace2 Monoclonal Antibodies as Pan-Sarbecovirus Prophylactic Agents

Background: Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, nearly all of these antibodies have been rendered obsolete by SARS-CoV-2 variants that evolved to resist similar, naturally occurring antibodies. Moreover, Most SARS-CoV-2 specific antibodies are inactive against divergent sarbecoviruses Methods: By immunizing mice that carry human immunoglobulin variable gene segments we generated a suite of fully human monoclonal antibodies that bind the human ACE2 receptor (hACE2) rather than the viral spike protein and were engineered to lack effector functions such as ADCC. Result(s): These ACE2 binding antibodies block infection by all hACE2 binding sarbecoviruses, including emergent SARS-CoV-2 variants, with a potency that of the most potent spike binding therapeutic antibodies. Structural and biochemical analyses revealed that the antibodies target an hACE2 epitope that engages SARS-CoV-2 spike. Importantly, the antibodies do not inhibit hACE2 enzymatic activity, nor do they induce ACE depletion from cell surfaces. The antibodies exhibit favorable pharmacology in human ACE2 knock in mice and provide near complete protection of hACE2 knock-in mice against SARS-CoV-2 infection. Conclusion(s): ACE2 binding antibodies should be useful prophylactic and treatment agents against any current and future SARS-CoV-2 variants, as well as hACE2-binding sarbecoviruses that might emerge as future pandemic threats.

Human monoclonal antibodies to the spike subdomain 1 neutralize SARS-CoV-2 and its variants of concern

Progress in the fight against COVID-19 is jeopardized by the emergence of SARS-CoV-2 variants that diminish or abolish the efficacy of vaccines and antiviral monoclonal antibodies. Novel immune therapies are therefore needed, that are broadly effective against present and future coronavirus threats. In principle, this could be achieved by focusing on portions of the virus that are both functionally relevant and averse to change. The Subdomain 1 (SD1) of SARS-CoV-2 Spike protein is adjacent to the RBD and its sequence is conserved across SARS-CoV-2 variants, except for substitutions A570D in Alpha (B.1.1.7) and T547K in Omicron BA.1 (B.1.1.529). In order to specifically identify and study human antibodies targeting SD1, we designed a flow cytometry-based strategy that combines negative selection of B cells binding to the Receptor Binding Domain (RBD) with positive selection of those binding to SD1-RBD fusion protein. Among the 15 produced human monoclonal antibodies, 6 are SD1-specific. 3 of them cross-react with SD1-RBDs corresponding to all six variants of concern and 2 are neutralizing SARS-CoV-2 pseudovirus. Antibody sd1.040 also neutralizes Delta, Omicron BA.1 and Omicron BA.2 pseudovirus, synergizes with an antibody to the RBD for neutralization, and protects mice when present in a bispecific antibody. Thus, naturally occurring antibodies can neutralize SARS-CoV-2 variants by binding to SD1 and can act synergistically against SARS-CoV-2 in preclinical models.