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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

Izadi, Arman LU ; Karami, Yasaman ; Bratanis, Eleni LU ; Wrighton, Sebastian LU orcid ; Khakzad, Hamed ; Nyblom, Maria ; Olofsson, Berit LU orcid ; Happonen, Lotta LU ; Tang, Di LU orcid and Sundwall, Martin LU orcid , et al. (2024) In Nature Communications 15. p.1-22
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
article number
3600
pages
1 - 22
publisher
Nature Publishing Group
external identifiers
  • pmid:38678029
  • scopus:85191631587
ISSN
2041-1723
DOI
10.1038/s41467-024-47928-8
project
Functional Impact of Immunoglobulin G subclass in Bacterial and viral Infections
Properties of Protective Antibody Responses against Bacterial Pathogens
language
English
LU publication?
yes
id
8f0da2eb-c108-4fb3-9a71-1bdd0da37c90
date added to LUP
2024-04-28 10:14:40
date last changed
2024-05-15 12:19:25
@article{8f0da2eb-c108-4fb3-9a71-1bdd0da37c90,
  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.}},
  author       = {{Izadi, Arman and Karami, Yasaman and Bratanis, Eleni and Wrighton, Sebastian and Khakzad, Hamed and Nyblom, Maria and Olofsson, Berit and Happonen, Lotta and Tang, Di and Sundwall, Martin and Godzwon, Magdalena and Chao, Yashuan and Gomez Toledo, Alejandro and Schmidt, Tobias and Ohlin, Mats and Nilges, Michael and Malmström, Johan and Bahnan, Wael and Shannon, Oonagh and Malmström, Lars and Nordenfelt, Pontus}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{04}},
  pages        = {{1--22}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-47928-8}},
  doi          = {{10.1038/s41467-024-47928-8}},
  volume       = {{15}},
  year         = {{2024}},
}