Clinical Results with a B Cell Activating Anti-CD73 Antibody for the Immunotherapy of COVID-19

  1. Richard A. Miller
  2. Pramod Guru
  3. Philippe Bauer
  4. Jorge Robles
  5. Christian Tomaszewski
  6. J. Scott Overcash
  7. Michael Waters
  8. Miriam Cameron
  9. Julián Olalla Sierra
  10. Haider Mashhedi
  11. Mehrdad Mobasher
  12. James Janc
  13. Jenny A. Rudnick
  14. Shenshen Hu
  15. William B. Jones
  16. Long Kwei
  17. Suresh Mahabhashyam
  18. Stephen B. Willingham
  19. Gerard Criner

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Abstract

Robust polyclonal humoral immune responses have the potential to generate a diverse set of antibodies to neutralize and eliminate viruses such as SARS-CoV-2 and protect against transmission, re-infection and the evolution of variants that evade immunity. CD73 is present on subsets of human B and T cells where it plays a role in lymphocyte activation and migration. CD73 also functions as an ectoenzyme that converts AMP into immunosuppressive adenosine. We have developed a humanized anti-CD73 antibody, mupadolimab (CPI-006), that blocks CD73 enzymatic activity and activates CD73 POS B cells, thereby inducing differentiation into plasmablasts, immunoglobulin class switching, and antibody secretion independent of the adenosine modulatory activity. These effects suggest mupadolimab may enhance the magnitude, diversity, and duration of anti-viral responses in patients with COVID-19. This hypothesis was tested in a dose escalation phase 1 trial in 29 hospitalized patients with COVID-19. Single doses of 0.3 mg/kg – 5 mg/kg mupadolimab were well tolerated with no drug related adverse events. Doses greater than 0.3 mg/kg resulted in rapid generation of IgG and IgM to SARS-CoV-2 significantly above titers measured in convalescent controls, with elevated IgG titers sustained for more than 6 months beyond presentation of symptoms. Based on these findings, a randomized double-blind, placebo-controlled Phase 3 study in hospitalized patients was initiated. The primary endpoint was proportion of patients alive and free from respiratory failure within 28 days. This trial was discontinued early during the period of waning COVID-19 incidence after enrolling 40 patients. Although underpowered, results from this trial suggest improvement in the primary and key secondary endpoints in patients treated with single doses of 2 mg/kg and 1 mg/kg compared to placebo. The presumed mechanism of action, stimulation of B cells, may represent a novel approach to immunotherapy of COVID-19 and other viral infections.

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  1. Version published to 10.1101/2021.09.13.21263406v2 on medRxiv
  2. ScreenIT

    SciScore for 10.1101/2021.09.13.21263406: (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.
    RandomizationMice were then randomized into two treatment groups: half the animals were dosed daily (i.p.) with 10 mg/kg mupadolimab, and half the animals were dosed daily with 10 mg/kg hIgG1 (BioXCell).
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Animals were cheek bled on days 1 (pre-bleed), 4, 8, 11 and 15 to assess anti-spike or anti-nucleocapsid (as a negative control) antibody production over time by ELISA.
    anti-spike
    suggested: None
    anti-nucleocapsid
    suggested: None
    Anti-SARS-CoV-2 antibody ELISA assays: ELISA was performed to measure the IgG and IgM to the receptor-binding domain (RBD) of the spike protein, full-length spike trimer of the SARS-CoV-2 virus.
    Anti-SARS-CoV-2
    suggested: None
    After three washes, the bound antibody was detected using anti-human IgG-horseradish peroxidase (HRP) conjugated secondary antibody (1:3000, Sigma-Aldrich,
    anti-human IgG-horseradish
    suggested: None
    A0170) or anti-human IgM HPR secondary antibody (1:3000, Sigma-Aldrich, A0420).
    anti-human IgM
    suggested: (Sigma-Aldrich Cat# A0420, RRID:AB_257886)
    A0420
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Neutralization activity was determined using heat inactivated serum (56°C, 30 min) mixed with pseudovirus before addition to HEK293T-hACE2 cells.
    HEK293T-hACE2
    suggested: RRID:CVCL_A7UK)
    Experimental Models: Organisms/Strains
    SentencesResources
    Preclinical mouse immunization model: NSG-SGM3 mice (Jackson Laboratories, stock #013062) were immunized with an emulsion of 50 ug full length spike protein from SARS-CoV-2 (ABClonal) and Freund’s Incomplete Adjuvant (Sigma) subcutaneously on both the left and right flank (25 μg/side).
    NSG-SGM3
    suggested: None
    Viral neutralization assays: SARS-CoV-2 spike pseudotyped lentivirus were produced with the Wuhan-Hu-1 (wild type), B.1.1.7 or B.1.351 variant spike as the envelope glycoprotein and the firefly luciferase gene as a reporter (BPS Bioscience)
    Wuhan-Hu-1
    suggested: None
    Software and Algorithms
    SentencesResources
    ID50 values were obtained by fitting the response data to a four-parameter logistic equation using GraphPad Prism version 8.4.3 for Windows, GraphPad Software, San Diego, California 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
    NCT04464395CompletedStudy of CPI-006 as Immunotherapy for Hospitalized COVID-19 …
    NCT04734873TerminatedCPI-006 Plus Standard of Care Versus Placebo Plus Standard o…

    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

    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.

  3. Version published to 10.1101/2021.09.13.21263406v1 on medRxiv