The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Nature Communications Année : 2024

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

Arman Izadi
Eleni Bratanis
Sebastian Wrighton
Maria Nyblom
  • Fonction : Auteur
Berit Olofsson
Lotta Happonen
Di Tang
Martin Sundwall
Yashuan Chao
Alejandro Gomez Toledo
Tobias Schmidt
Mats Ohlin
Johan Malmström
Wael Bahnan
  • Fonction : Auteur
Lars Malmström
Pontus Nordenfelt
  • Fonction : Auteur correspondant
  • PersonId : 1345202

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Résumé

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, IgGh xx . 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. IgGh 47 shows improved protection against S. pyogenes in a systemic infection mouse model, suggesting that IgGh 47 has promise as a preclinical therapeutic candidate. Importantly, the enhanced opsonic function of IgGh 47 is generalizable to diverse S. pyogenes strains from clinical isolates. We generated IgGh 47 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 IgGh 47 subclass in two distant biological systems provides new insights into antibody function.
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hal-04567019 , version 1 (02-05-2024)

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Arman Izadi, Yasaman Karami, Eleni Bratanis, Sebastian Wrighton, Hamed Khakzad, et al.. The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies. Nature Communications, 2024, 15 (1), pp.3600. ⟨10.1038/s41467-024-47928-8⟩. ⟨hal-04567019⟩
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