Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection

Wei Li, Chuan Chen, Aleksandra Drelich, David R. Martinez, Lisa E. Gralinski, Zehua Suna, Alexandra Schafer, Swarali S. Kulkarni, Xianglei Liu, Sarah R. Leist, Doncho V. Zhelev, Liyong Zhang, Ye Jin Kim, Eric C. Peterson, Alex Conard, John W. Mellors, Chien Te K. Tseng, Darryl Falzarano, Ralph S. Baric, Dimiter S. Dimitrov

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)29832-29838
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number47
DOIs
StatePublished - Nov 24 2020

Keywords

  • Animal models
  • Coronaviruses
  • SARS-CoV-2
  • Therapeutic antibodies

ASJC Scopus subject areas

  • General

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