TY - JOUR TI - Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection AU - Li, Wei AU - Chen, Chuan AU - Drelich, Aleksandra AU - Martinez, David R. AU - Gralinski, Lisa E. AU - Sun, Zehua AU - Schäfer, Alexandra AU - Kulkarni, Swarali S. AU - Liu, Xianglei AU - Leist, Sarah R. AU - Zhelev, Doncho V. AU - Zhang, Liyong AU - Kim, Ye-Jin AU - Peterson, Eric C. AU - Conard, Alex AU - Mellors, John W. AU - Tseng, Chien-Te K. AU - Falzarano, Darryl AU - Baric, Ralph S. AU - Dimitrov, Dimiter S. T2 - Proceedings of the National Academy of Sciences AB - 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. DA - 2020/11/24/ PY - 2020 DO - 10.1073/pnas.2010197117 DP - www.pnas.org VL - 117 IS - 47 SP - 29832 EP - 29838 J2 - PNAS LA - en SN - 0027-8424, 1091-6490 UR - https://www.pnas.org/content/117/47/29832 Y2 - 2020/11/25/23:39:52 KW - SARS-CoV-2 KW - animal models KW - coronaviruses KW - therapeutic antibodies ER -