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

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. Marijnissen, Janine Schuurman, Frank J. Beurskens, Priscilla F. Kerkman and Suzan H. M. Rooijakkers ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52372-9

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