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The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies

Author

Listed:
  • Arman Izadi

    (Lund University)

  • Yasaman Karami

    (CNRS, Inria, LORIA
    Department of Structural Biology and Chemistry)

  • Eleni Bratanis

    (Lund University)

  • Sebastian Wrighton

    (Lund University)

  • Hamed Khakzad

    (CNRS, Inria, LORIA)

  • Maria Nyblom

    (Lund University)

  • Berit Olofsson

    (Lund University)

  • Lotta Happonen

    (Lund University)

  • Di Tang

    (Lund University)

  • Martin Sundwall

    (Lund University)

  • Magdalena Godzwon

    (Lund University)

  • Yashuan Chao

    (Lund University)

  • Alejandro Gomez Toledo

    (Lund University)

  • Tobias Schmidt

    (Lund University)

  • Mats Ohlin

    (Lund University)

  • Michael Nilges

    (Department of Structural Biology and Chemistry)

  • Johan Malmström

    (Lund University)

  • Wael Bahnan

    (Lund University)

  • Oonagh Shannon

    (Lund University
    Malmö University)

  • Lars Malmström

    (Lund University)

  • Pontus Nordenfelt

    (Lund University
    Lund University)

Abstract

Streptococcus pyogenes can cause invasive disease with high mortality despite adequate antibiotic treatments. To address this unmet need, we have previously generated an opsonic IgG1 monoclonal antibody, Ab25, targeting the bacterial M protein. Here, we engineer the IgG2-4 subclasses of Ab25. Despite having reduced binding, the IgG3 version promotes stronger phagocytosis of bacteria. Using atomic simulations, we show that IgG3’s Fc tail has extensive movement in 3D space due to its extended hinge region, possibly facilitating interactions with immune cells. We replaced the hinge of IgG1 with four different IgG3-hinge segment subclasses, IgGhxx. Hinge-engineering does not diminish binding as with IgG3 but enhances opsonic function, where a 47 amino acid hinge is comparable to IgG3 in function. IgGh47 shows improved protection against S. pyogenes in a systemic infection mouse model, suggesting that IgGh47 has promise as a preclinical therapeutic candidate. Importantly, the enhanced opsonic function of IgGh47 is generalizable to diverse S. pyogenes strains from clinical isolates. We generated IgGh47 versions of anti-SARS-CoV-2 mAbs to broaden the biological applicability, and these also exhibit strongly enhanced opsonic function compared to the IgG1 subclass. The improved function of the IgGh47 subclass in two distant biological systems provides new insights into antibody function.

Suggested Citation

  • Arman Izadi & Yasaman Karami & Eleni Bratanis & Sebastian Wrighton & Hamed Khakzad & Maria Nyblom & Berit Olofsson & Lotta Happonen & Di Tang & Martin Sundwall & Magdalena Godzwon & Yashuan Chao & Ale, 2024. "The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47928-8
    DOI: 10.1038/s41467-024-47928-8
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