Intranasal Administration of a Monoclonal Neutralizing Antibody Protects Mice against SARS-CoV-2 Infection

  1. Sandro Halwe
  2. Alexandra Kupke
  3. Kanika Vanshylla
  4. Falk Liberta
  5. Henning Gruell
  6. Matthias Zehner
  7. Cornelius Rohde
  8. Verena Krähling
  9. Michelle Gellhorn Serra
  10. Christoph Kreer
  11. Michael Klüver
  12. Lucie Sauerhering
  13. Jörg Schmidt
  14. Zheng Cai
  15. Fei Han
  16. David Young
  17. Guangwei Yang
  18. Marek Widera
  19. Manuel Koch
  20. Anke Werner
  21. Lennart Kämper
  22. Nico Becker
  23. Michael S. Marlow
  24. Markus Eickmann
  25. Sandra Ciesek
  26. Felix Schiele
  27. Florian Klein
  28. Stephan Becker

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Abstract

Despite the recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of the SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2, retains full activity against the variant of concern (VOC) B.1.1.7 and still neutralizes the VOC B.1.351, although with reduced potency. Importantly, not only systemic but also intranasal application of DZIF-10c abolished the presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology when administered prophylactically. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.

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  1. Version published to 10.3390/v13081498
  2. ScreenIT

    SciScore for 10.1101/2021.06.09.447662: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Next day, plates were blocked with 5% BSA in PBS for 60 min at RT, incubated with primary antibody (starting concentration 10 µg/ml) in PBS for 120 min and secondary antibody (anti-human IgG-HRP; Southern Biotech 2040-05) diluted 1:2500 in 1% BSA in PBS for 60 min at RT.
    anti-human IgG-HRP
    suggested: (SouthernBiotech Cat# 2040-05, RRID:AB_2795644)
    Application of monoclonal antibodies (DZIF-10c or IgG isotype control) was performed via the intranasal or the intraperitoneal route at a dose of 40 mg/KG.
    DZIF-10c or IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Pseudovirus neutralization assay: SARS-CoV-2 pseudovirus particles were generated by co-transfection of individual plasmids encoding HIV Tat, HIV Gag/Pol, HIV Rev, luciferase followed by an IRES and ZsGreen, and the SARS-CoV-2 spike protein (23) into HEK 293T cells using the FuGENE 6 Transfection Reagent (
    HEK 293T
    suggested: CCLV Cat# CCLV-RIE 1018, RRID:CVCL_0063)
    For testing neutralization potency of DZIF-10c, serial dilutions of DZIF-10c were co-incubated with pseudovirus supernatants for 1 h at 37°C, following which 293T-ACE-2 cells were added.
    293T-ACE-2
    suggested: RRID:CVCL_YZ65)
    Subsequently, Vero E6 cells (Vero C1008, ATCC, Cat#CRL-1586, RRID: CVCL_0574) were washed with PBSdef, trypsinized and diluted in DMEM with 10% FBS, 1% glutamine and 1% penicillin/streptomycin.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Vero
    detected: (IZSLER Cat# BS CL 87, RRID:CVCL_0574)
    C1008
    suggested: ATCC Cat# CRL-1586, RRID:CVCL_0574)
    Experimental Models: Organisms/Strains
    SentencesResources
    FAM-ACACTAGCCATCCTTACTGCGCTTCG-BBQ Pharmacokinetic Profile of DZIF-10c in NRG and FcRn Mice: NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl/SzJ (NRG) and B6.Cg-Fcgrttm1Dcr Prkdcscid Tg(FCGRT)32Dcr/DcrJ (FcRn) mice (The Jackson Laboratory) were bred and maintained at the Decentralized Animal Husbandry Network of the University of Cologne, and the experiments were authorized by the State Agency for Nature, Environmental Protection, and Consumer Protection North Rhine-Westphalia (84-02.04.2015.
    NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl/SzJ
    suggested: RRID:IMSR_JAX:007799)
    B6.Cg-Fcgrttm1Dcr Prkdcscid Tg(FCGRT)32Dcr/DcrJ
    suggested: RRID:IMSR_JAX:018441)
    Briefly, 6-8 week old BALB/c mice were purchased from Charles River Laboratories and housed under specific pathogen-free conditions in isocages in the animal facility at the Institute of Virology Marburg.
    BALB/c
    suggested: RRID:IMSR_ORNL:BALB/cRl)
    Software and Algorithms
    SentencesResources
    Single particle data processing was performed in cryoSPARC v2.15 (Structura Biotechnology Inc.) as described below.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    All statistical analyses were performed using GraphPad Prism. Supplementary Methods: Fig.
    GraphPad Prism
    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
    NCT04631705RecruitingSARS-CoV-2-Neutralizing Monoclonal COVID-19 Antibody DZIF-10…

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2021.06.09.447662v1 on bioRxiv