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Agnostic B cell selection approach identifies antibodies against K. pneumoniae that synergistically drive complement activation

Author

Listed:
  • Sjors P. A. Lans

    (University Medical Center Utrecht, Utrecht University)

  • Bart W. Bardoel

    (University Medical Center Utrecht, Utrecht University)

  • Maartje Ruyken

    (University Medical Center Utrecht, Utrecht University)

  • Carla J. C. Haas

    (University Medical Center Utrecht, Utrecht University)

  • Stan Baijens

    (University Medical Center Utrecht, Utrecht University)

  • Remy M. Muts

    (University Medical Center Utrecht, Utrecht University)

  • Lisette M. Scheepmaker

    (University Medical Center Utrecht, Utrecht University)

  • Piet C. Aerts

    (University Medical Center Utrecht, Utrecht University)

  • Marije F. L. van ’t Wout

    (University Medical Center Utrecht, Utrecht University)

  • Johannes Preiner

    (University of Applied Sciences Upper Austria)

  • Renoud J. Marijnissen

    (Genmab)

  • Janine Schuurman

    (Genmab)

  • Frank J. Beurskens

    (Genmab)

  • Priscilla F. Kerkman

    (University Medical Center Utrecht, Utrecht University)

  • Suzan H. M. Rooijakkers

    (University Medical Center Utrecht, Utrecht University)

Abstract

Antibody-dependent complement activation plays a key role in the natural human immune response to infections. Currently, the understanding of which antibody-antigen combinations drive a potent complement response on bacteria is limited. Here, we develop an antigen-agnostic approach to stain and single-cell sort human IgG memory B cells recognizing intact bacterial cells, keeping surface antigens in their natural context. With this method we successfully identified 29 antibodies against K. pneumoniae, a dominant cause of hospital-acquired infections with increasing antibiotic resistance. Combining genetic tools and functional analyses, we reveal that the capacity of antibodies to activate complement on K. pneumoniae critically depends on their antigenic target. Furthermore, we find that antibody combinations can synergistically activate complement on K. pneumoniae by strengthening each other’s binding in an Fc-independent manner. Understanding the molecular basis of effective complement activation by antibody combinations to mimic a polyclonal response could accelerate the development of antibody-based therapies against problematic infections.

Suggested Citation

  • Sjors P. A. Lans & Bart W. Bardoel & Maartje Ruyken & Carla J. C. Haas & Stan Baijens & Remy M. Muts & Lisette M. Scheepmaker & Piet C. Aerts & Marije F. L. van ’t Wout & Johannes Preiner & Renoud J. , 2024. "Agnostic B cell selection approach identifies antibodies against K. pneumoniae that synergistically drive complement activation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52372-9
    DOI: 10.1038/s41467-024-52372-9
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    References listed on IDEAS

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    1. Leoni Abendstein & Douwe J. Dijkstra & Rayman T. N. Tjokrodirijo & Peter A. Veelen & Leendert A. Trouw & Paul J. Hensbergen & Thomas H. Sharp, 2023. "Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
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