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

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  • Li, Wei
    • Other Affiliation: University of Pittsburgh Medical School
  • Chen, Chuan
    • Other Affiliation: University of Pittsburgh Medical School
  • Drelich, Aleksandra
    • Other Affiliation: Galveston National Laboratory
  • Martinez, David R.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Gralinski, Lisa E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Sun, Zehua
    • Other Affiliation: University of Pittsburgh Medical School
  • Schäfer, Alexandra
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Kulkarni, Swarali S.
    • Other Affiliation: University of Saskatchewan
  • Liu, Xianglei
    • Other Affiliation: University of Pittsburgh Medical School
  • Leist, Sarah R.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Zhelev, Doncho V.
    • Other Affiliation: University of Pittsburgh Medical School
  • Zhang, Liyong
    • Other Affiliation: University of Pittsburgh Medical School
  • Kim, Ye-Jin
    • Other Affiliation: University of Pittsburgh Medical School
  • Peterson, Eric C.
    • Other Affiliation: Abound Bio
  • Conard, Alex
    • Other Affiliation: Abound Bio
  • Mellors, John W.
    • Other Affiliation: University of Pittsburgh Medical School
  • Tseng, Chien-Te K.
    • Other Affiliation: University of Pittsburgh Medical School
  • Falzarano, Darryl
    • Other Affiliation: University of Saskatchewan
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Dimitrov, Dimiter S.
    • Other Affiliation: University of Pittsburgh Medical School
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.
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  • Article
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  • In Copyright
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  • Attribution 3.0 United States
Journal title
  • Proceedings of the National Academy of Sciences
Journal volume
  • 117
Journal issue
  • 47
Language
  • English
ISSN
  • 0027-8424, 1091-6490

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