Isotype conversion of Staphylococcal-specific IgG into IgM broadens the reactivity to other bacterial pathogens

Cell Reports Medicine, vol. 6, pp. 102414

Abstract

Therapeutic antibodies are actively explored as alternative to treat or prevent bacterial infections. However, the narrow antigen specificity of IgG in combination with broad diversity in bacterial surface structures currently hampers the development of therapeutic antibodies against bacteria. Here we reveal that isotype conversion of three highly specific anti-staphylococcal antibodies from IgG into IgM does not only affect Fc effector functions but also modifies the interaction of Fab domains with bacterial surface antigens. These converted IgMs gain cross-reactivity for a broad range of bacterial species, including Gram-negatives such as Escherichia coli and Neisseria meningitidis and even protect against invasive infection with Streptococcus pyogenes in vivo. Mechanistic studies show that enhanced cross-specificity by IgM is conferred by changed ligand specificity and multivalent binding to high-density antigens. Altogether, these findings provide important insights for the development of antibody therapy for bacterial infections.

Authors 15

1. Remy M. Muts

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands

2. Astrid Hendriks

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

3. Josefien W. Hommes

   University of Calgary

   Affiliation as printed

   Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada

4. Max L.B. Grönloh

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands

5. Douwe J. Dijkstra

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands

6. Carla J. C. de Haas

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands

7. Piet C. Aerts

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands

8. Eduard H.T.M. Ebberink

   Utrecht University

   Affiliation as printed

   Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands

9. Albert J. R. Heck

   Utrecht University · Netherlands Proteomics Centre

   Affiliation as printed

   Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands; Netherlands Proteomic Center, 3584 CH Utrecht, the Netherlands

10. Haoru Zhuang Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, the Netherlands

11. Jeroen D. C. Codée Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, the Netherlands

12. Bas G. J. Surewaard

    University of Calgary

    Affiliation as printed

    Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada

13. Dani A. C. Heesterbeek

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands

14. Nina M. van Sorge

    Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam UMC, Amsterdam, the Netherlands

15. Suzan H. M. Rooijakkers corresponding

    University Medical Center Utrecht

    Affiliation as printed

    Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: s.h.m.rooijakkers@umcutrecht.nl