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Implementing a method for engineering multivalency to substantially enhance binding of clinical trial anti-SARS-CoV-2 antibodies to wildtype spike and variants of concern proteins

Authors
  • Leach, Adam1
  • Miller, Ami1, 2
  • Bentley, Emma3
  • Mattiuzzo, Giada3
  • Thomas, Jemima1
  • McAndrew, Craig1
  • Van Montfort, Rob1
  • Rabbitts, Terence1
  • 1 Institute of Cancer Research, 15 Cotswold Road, Sutton, London, SM2 5NG, UK , London (United Kingdom)
  • 2 Evotec, 114 Innovation Dr, Milton Park, Abingdon, OX14 4RZ, UK , Abingdon (United Kingdom)
  • 3 National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Hertfordshire, EN6 3QG, UK , Hertfordshire (United Kingdom)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
May 18, 2021
Volume
11
Issue
1
Identifiers
DOI: 10.1038/s41598-021-89887-w
Source
Springer Nature
License
Green

Abstract

Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 disease. Therapeutic antibodies are being developed that interact with the viral spike proteins to limit viral infection of epithelium. We have applied a method to dramatically improve the performance of anti-SARS-CoV-2 antibodies by enhancing avidity through multimerization using simple engineering to yield tetrameric antibodies. We have re-engineered six anti-SARS-CoV-2 antibodies using the human p53 tetramerization domain, including three clinical trials antibodies casirivimab, imdevimab and etesevimab. The method yields tetrameric antibodies, termed quads, that retain efficient binding to the SARS-CoV-2 spike protein, show up to two orders of magnitude enhancement in neutralization of pseudovirus infection and retain potent interaction with virus variant of concern spike proteins. The tetramerization method is simple, general and its application is a powerful methodological development for SARS-CoV-2 antibodies that are currently in pre-clinical and clinical investigation.

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