A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients by phage display is binding to the ACE2-RBD interface and is tolerant to most known recently emerging RBD mutations

  1. Federico Bertoglio
  2. Viola Fühner
  3. Maximilian Ruschig
  4. Philip Alexander Heine
  5. Leila Abasi
  6. Thomas Klünemann
  7. Ulfert Rand
  8. Doris Meier
  9. Nora Langreder
  10. Stephan Steinke
  11. Rico Ballmann
  12. Kai-Thomas Schneider
  13. Kristian Daniel Ralph Roth
  14. Philipp Kuhn
  15. Peggy Riese
  16. Dorina Schäckermann
  17. Janin Korn
  18. Allan Koch
  19. M. Zeeshan Chaudhry
  20. Kathrin Eschke
  21. Yeonsu Kim
  22. Susanne Zock-Emmenthal
  23. Marlies Becker
  24. Margitta Scholz
  25. Gustavo Marçal Schmidt Garcia Moreira
  26. Esther Veronika Wenzel
  27. Giulio Russo
  28. Hendrikus S.P. Garritsen
  29. Sebastian Casu
  30. Andreas Gerstner
  31. Günter Roth
  32. Julia Adler
  33. Jakob Trimpert
  34. Andreas Hermann
  35. Thomas Schirrmann
  36. Stefan Dübel
  37. André Frenzel
  38. Joop Van den Heuvel
  39. Luka Čičin-Šain
  40. Maren Schubert
  41. Michael Hust

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Abstract

The novel betacoranavirus SARS-CoV-2 causes a form of severe pneumonia disease, termed COVID-19 (coronavirus disease 2019). Recombinant human antibodies are proven potent neutralizers of viruses and can block the interaction of viral surface proteins with their host receptors. To develop neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor binding domain (RBD) of the S1 subunit of the viral spike (S) protein were selected by phage display. The selected antibodies were produced in the scFv-Fc format and 30 showed more than 80% inhibition of spike (S1-S2) binding to cells expressing ACE2, assessed by flow cytometry screening assay. The majority of these inhibiting antibodies are derived from the VH3-66 V-gene. The antibody STE90-C11 showed a sub nM IC50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody was demonstrated in the Syrian hamster and in the hACE2 mice model using a silenced human IgG1 Fc part. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD was solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibtion of STE90-C11 is not blocked by many known RBD mutations including N439K, L452R, E484K or L452R+E484Q (emerging B.1.617). STE90-C11 derived human IgG1 with FcγR silenced Fc (COR-101) is currently undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19.

In Brief

Human antibodies were selected from convalescent COVID-19 patients using antibody phage display. The antibody STE90-C11 is neutralizing authentic SARS-CoV-2 virus in vitro and in vivo and the crystal structure of STE90-C11 in complex with SARS-CoV-2-RBD revealed that this antibody is binding in the RBD-ACE2 interface. S1 binding of STE90-C11 and inhibition of ACE2 binding is not blocked by many known RBD mutations.

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    SciScore for 10.1101/2020.12.03.409318: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 54. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.12.03.409318 on bioRxiv