Multivalency transforms SARS-CoV-2 antibodies into ultrapotent neutralizers

  1. Edurne Rujas
  2. Iga Kucharska
  3. Yong Zi Tan
  4. Samir Benlekbir
  5. Hong Cui
  6. Tiantian Zhao
  7. Gregory A. Wasney
  8. Patrick Budylowski
  9. Furkan Guvenc
  10. Jocelyn C. Newton
  11. Taylor Sicard
  12. Anthony Semesi
  13. Krithika Muthuraman
  14. Amy Nouanesengsy
  15. Clare Burn Aschner
  16. Katherine Prieto
  17. Stephanie A. Bueler
  18. Sawsan Youssef
  19. Sindy Liao-Chan
  20. Jacob Glanville
  21. Natasha Christie-Holmes
  22. Samira Mubareka
  23. Scott D. Gray-Owen
  24. John L. Rubinstein
  25. Bebhinn Treanor
  26. Jean-Philippe Julien

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Abstract

SARS-CoV-2, the virus responsible for COVID-19, has caused a global pandemic. Antibodies can be powerful biotherapeutics to fight viral infections. Here, we use the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers. Using this platform, half-maximal inhibitory concentration (IC 50 ) values as low as 9 × 10 − 14 M are achieved as a result of up to 10,000-fold potency enhancements compared to corresponding IgGs. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and IgG-like bioavailability. The MULTi-specific, multi-Affinity antiBODY (Multabody or MB) platform thus uniquely leverages binding avidity together with multi-specificity to deliver ultrapotent and broad neutralizers against SARS-CoV-2. The modularity of the platform also makes it relevant for rapid evaluation against other infectious diseases of global health importance. Neutralizing antibodies are a promising therapeutic for SARS-CoV-2.

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  3. Version published to 10.1038/s41467-021-23825-2
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    SciScore for 10.1101/2020.10.15.341636: (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

    Software and Algorithms
    SentencesResources
    Materials and Methods:
    Methods
    suggested: None

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The fact that 2 out of 20 SARS-CoV-2 RBD binders were not rescued by the MB platform also suggests limitations based on mAb sequences and binding properties. Nevertheless, the capacity of the MB to transform avidity into neutralization potency across a range of epitope specificities on the SARS-CoV-2 Spike highlights the potential for using this technology broadly. It will be interesting to explore the potency-enhancement capacity of the MB platform against viruses with low surface spike density like HIV41, or against other targets like the tumor necrosis factor receptor superfamily, where bivalency of conventional antibodies limits their efficient activation42. Virus escape can arise in response to selective pressure from treatments or during natural selection. A conventional approach to combat escape mutants is the use of antibody cocktails targeting different epitopes. MBs showed a lower susceptibility to S mutations in comparison to their parental IgGs, presumably because the loss in affinity was compensated by enhanced binding avidity. Hence, when used in cocktails, the MB overcame viral sequence variability with exceptional potency. In addition, the split MB design allows combination of multiple antibody specificities within a single multimerized molecule resulting in similar potency and breadth as the MB cocktails. To our knowledge, these MBs represent the first tri-specifics described against SARS-CoV-2. Multi-specificity within the same particle could offer additiona...

    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 46. 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.
    • Thank you for including a protocol registration statement.

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  5. Version published to 10.1101/2020.10.15.341636v1 on bioRxiv