@article{06e5137655a548268cf9c16471b61b72,
title = "Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection",
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.",
keywords = "Animal models, Coronaviruses, SARS-CoV-2, Therapeutic antibodies",
author = "Wei Li and Chuan Chen and Aleksandra Drelich and Martinez, {David R.} and Gralinski, {Lisa E.} and Zehua Suna and Alexandra Schafer and Kulkarni, {Swarali S.} and Xianglei Liu and Leist, {Sarah R.} and Zhelev, {Doncho V.} and Liyong Zhang and Kim, {Ye Jin} and Peterson, {Eric C.} and Alex Conard and Mellors, {John W.} and Tseng, {Chien Te K.} and Darryl Falzarano and Baric, {Ralph S.} and Dimitrov, {Dimiter S.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank the members of the Center for Antibody Therapeutics: Megan Shi, Cynthia Adams, Du-San Baek, and Xiaojie Chu for their help with some of the experiments and helpful discussions. We also thank Rui Gong from the Institute of Virology in Wuhan and Rachel Fong from Integral Molecular for helpful suggestions. This work was supported by the University of Pittsburgh Medical Center. We thank Jocelyne Lew and Vinoth Manoharan for technical assistance and the members of the Clinical Research and Animal Care team at VIDO-InterVac, as well as Yanyun Huang and Dale Godson (Prairie Diagnostic Services, Inc.). D.R.M. is funded by NIH grant F32 AI152296, a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award, and was supported by NIH, National Institute of Allergy and Infectious Diseases grant T32 AI007151. R.S.B. is supported by NIH grants AI132178 and AI108197. Some monoclonal antibodies were generated by the UNC Protein Expression and Purification core facility, which is funded by NIH grant P30CA016086. Funding Information: We thank the members of the Center for Antibody Therapeutics:Megan Shi, Cynthia Adams, Du-San Baek, and Xiaojie Chu for their help with some of the experiments and helpful discussions. We also thank Rui Gong from the Institute of Virology in Wuhan and Rachel Fong from Integral Molecular for helpful suggestions. This work was supported by the University of Pittsburgh Medical Center. We thank Jocelyne Lew and Vinoth Manoharan for technical assistance and the members of the Clinical Research and Animal Care team at VIDO-InterVac, as well as Yanyun Huang and Dale Godson (Prairie Diagnostic Services, Inc.). D.R.M. is funded by NIH grant F32 AI152296, a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award, and was supported by NIH, National Institute of Allergy and Infectious Diseases grant T32 AI007151. R.S.B. is supported by NIH grants AI132178 and AI108197. Some monoclonal antibodies were generated by the UNC Protein Expression and Purification core facility, which is funded by NIH grant P30CA016086. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = nov,
day = "24",
doi = "10.1073/pnas.2010197117",
language = "English (US)",
volume = "117",
pages = "29832--29838",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "47",
}