IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern

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  • Chang, Matthew R.
    • Other Affiliation: Dana-Farber Cancer Institute
  • Tomasovic, Luke
    • Other Affiliation: Dana-Farber Cancer Institute
  • Kuzmina, Natalia A.
    • Other Affiliation: University of Texas Medical Branch
  • Ronk, Adam J.
    • Other Affiliation: University of Texas Medical Branch
  • Byrne, Patrick O.
    • Other Affiliation: University of Texas, Austin
  • Johnson, Rebecca
    • Other Affiliation: Boston University
  • Storm, Nadia
    • Other Affiliation: Boston University
  • Olmedillas, Eduardo
    • Other Affiliation: La Jolla Institute for Immunology
  • Hou, Yixuan J.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Schäfer, Alexandra
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Leist, Sarah R.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Tse, Longping V.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Ke, Hanzhong
    • Other Affiliation: Dana-Farber Cancer Institute
  • Coherd, Christian
    • Other Affiliation: Dana-Farber Cancer Institute
  • Nguyen, Katrina
    • Other Affiliation: Dana-Farber Cancer Institute
  • Kamkaew, Maliwan
    • Other Affiliation: Dana-Farber Cancer Institute
  • Honko, Anna
    • Other Affiliation: Boston University
  • Zhu, Quan
    • Other Affiliation: Dana-Farber Cancer Institute
  • Alter, Galit
    • Other Affiliation: Ragon Institute of MGH, MIT and Harvard
  • Saphire, Erica Ollmann
    • Other Affiliation: La Jolla Institute for Immunology
  • McLellan, Jason S.
    • Other Affiliation: University of Texas, Austin
  • Griffiths, Anthony
    • Other Affiliation: Boston University
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Bukreyev, Alexander
    • Other Affiliation: University of Texas Medical Branch
  • Marasco, Wayne A.
    • Other Affiliation: Dana-Farber Cancer Institute,
Abstract
  • Monoclonal antibodies are a promising approach to treat COVID-19, however the emergence of SARS-CoV-2 variants has challenged the efficacy and future of these therapies. Antibody cocktails are being employed to mitigate these challenges, but neutralization escape remains a major challenge and alternative strategies are needed. Here we present two anti-SARS-CoV-2 spike binding antibodies, one Class 1 and one Class 4, selected from our non-immune human single-chain variable fragment (scFv) phage library, that are engineered into four, fully-human IgG-like bispecific antibodies (BsAb). Prophylaxis of hACE2 mice and post-infection treatment of golden hamsters demonstrates the efficacy of the monospecific antibodies against the original Wuhan strain, while promising in vitro results with the BsAbs demonstrate enhanced binding and distinct synergistic effects on neutralizing activity against circulating variants of concern. In particular, one BsAb engineered in a tandem scFv-Fc configuration shows synergistic neutralization activity against several variants of concern including B.1.617.2. This work provides evidence that synergistic neutralization can be achieved using a BsAb scaffold, and serves as a foundation for the future development of broadly reactive BsAbs against emerging variants of concern.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
Journal title
  • Nature Communications
Journal volume
  • 13
Journal issue
  • 1
Page start
  • 5814
Language
  • English
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  • Publisher
ISSN
  • 2041-1723

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