Significance Effective therapies are urgently needed for COVID-19. We rapidly (within a week) identified a fully human monoclonal germline-like antibody (ab1) from phage-displayed libraries that potently inhibited mouse ACE2-adapted SARS-CoV-2 replication in wild-type BALB/c mice and native virus in transgenic mice expressing human ACE2 as well as in hamsters when administered before virus challenge. It was also effective when administered after virus infection of hamsters, although at lower efficacy than when used prophylactically. Ab1 was highly specific and did not bind to human cell membrane-associated proteins. It also exhibited good developability properties including complete lack of aggregation. Ab1 has potential for prophylaxis and therapy of COVID-19 alone or in combination with other agents. Effective therapies are urgently needed for the SARS-CoV-2/COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. A high-affinity Fab was selected from one of the libraries and converted to a full-size antibody, IgG1 ab1, which competed with human ACE2 for binding to RBD. It potently neutralized replication-competent SARS-CoV-2 but not SARS-CoV, as measured by two different tissue culture assays, as well as a replication-competent mouse ACE2-adapted SARS-CoV-2 in BALB/c mice and native virus in hACE2-expressing transgenic mice showing activity at the lowest tested dose of 2 mg/kg. IgG1 ab1 also exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection. The mechanism of neutralization is by competition with ACE2 but could involve antibody-dependent cellular cytotoxicity (ADCC) as IgG1 ab1 had ADCC activity in vitro. The ab1 sequence has a relatively low number of somatic mutations, indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 did not aggregate, did not exhibit other developability liabilities, and did not bind to any of the 5,300 human membrane-associated proteins tested. These results suggest that IgG1 ab1 has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 d of availability of antigen for panning) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.
【저자키워드】 SARS-CoV-2, Coronaviruses, animal models, therapeutic antibodies, 【초록키워드】 COVID-19, Efficacy, ACE2, pandemic, therapy, Vaccines, antibody, SARS-CoV, hamsters, neutralization, SARS-COV-2 infection, Proteins, in vitro, Prophylactic, virus, hACE2, Receptor binding domain, Antigen, Prophylaxis, human ACE2, Protein, Culture, RBD, Human monoclonal antibody, ADCC, glycoprotein, virus infection, hamster, SARS-CoV-2 infections, SARS-CoV-2 replication, mechanism, mAbs, antibody-dependent cellular cytotoxicity, IgG1, monoclonal, binding, SARS-CoV-2 spike, mAb, Fab, human monoclonal antibodies, Combination, dose, tissue culture, somatic mutations, tissue, ADCC activity, therapeutic efficacy, sequence, transgenic mice, aggregation, wild-type, BALB/c mice, aggregate, competition, microbes, human cell, public health threat, scFv, replication-competent SARS-CoV-2, Administered, Complete, effective, neutralized, lowest, human cell membrane, tested, lack, assays, inhibited, exhibited, expressing, elicited, Ab1, prophylactically, Significance, the SARS-CoV-2, was selected, 【제목키워드】 animal model, Prophylactic, Rapid,