XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2 Spike receptor-binding domain, targets multiple epitopes and broadly neutralizes variants

  1. Bernard Vanhove
  2. Stéphane Marot
  3. Ray T. So
  4. Benjamin Gaborit
  5. Gwénaëlle Evanno
  6. Isabelle Malet
  7. Guillaume Lafrogne
  8. Edwige Mevel
  9. Carine Ciron
  10. Pierre-Joseph Royer
  11. Elsa Lheriteau
  12. François Raffi
  13. Roberto Bruzzone
  14. Chris Ka Pun Mok
  15. Odile Duvaux
  16. Anne-Geneviève Marcelin
  17. Vincent Calvez

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Abstract

Amino acid substitutions and deletions in Spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBM), in direct contact sites with the Angiotensin Converting Enzyme-2 (ACE-2). Therefore, in Spike/ACE2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study with the Beta strain on Vero E6 cells conducted over 1 month, no mutation was associated with addition of increasing doses XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in a phase 2a-2b ( NCT04453384 ) where safety was already demonstrated and in an ongoing 2/3 trial ( NCT04928430 ) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (Covid-19) including the different variants of concern identified so far.

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  1. ScreenIT

    SciScore for 10.1101/2021.04.02.437747: (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.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Intermediate R&D preparations of swine glyco-humanized polyclonal antibody against SARS-CoV-2 have been prepared, presenting variable anti-SARS-CoV-2 binding activities 17.
    SARS-CoV-2
    suggested: None
    anti-SARS-CoV-2 binding activities 17
    suggested: None
    Spike/ACE-2 neutralization assay: An assay was developed to assess the properties of anti-SARS-CoV-2 spike antibodies to inhibit binding of ACE-2 to immobilized spike.
    anti-SARS-CoV-2 spike
    suggested: None
    Anti-Spike RBD antibodies diluted in PBS-Tween-0.05%-1% skimmed milk (dilution range between 50 and 0.39 µg/mL) were then added and incubated for 30 min.
    Anti-Spike RBD
    suggested: None
    After 1h incubation at room temperature and 3 washes, the mouse Fc tag was revealed with a specific HRP-conjugated anti-mouse IgG secondary antibody (diluted in in PBS-Tween-0.05%-1% skimmed milk powder at 1:1000, incubated 1h at RT and washed 3 times).
    anti-mouse IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Viral stocks were generated using one passage of isolates on Vero cells.
    Vero
    suggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)
    CPE reduction assay was performed as follows: Vero E6 cells were seeded in 96-well clusters at a density of 5,000 cells/well 2 days before infection.
    Vero E6
    suggested: None
    Software and Algorithms
    SentencesResources
    IC50 were analyzed by nonlinear regression using a four-parameter dosage-response variable slope model with the GraphPad Prism 8.0.2 software (GraphPad Software, USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04453384RecruitingStudy to Evaluate the Safety and Efficacy of XAV-19 in Patie…
    NCT04469179Active, not recruitingSafety, Tolerability, and Pharmacokinetics of SAB-185 in Amb…

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

    Results from JetFighter: We did not find any issues relating to colormaps.

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.04.02.437747 on bioRxiv