The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8f0da2eb-c108-4fb3-9a71-1bdd0da37c90
- author
- organization
-
- Quantitative immunobiology (research group)
- epIgG (research group)
- Structural Infection Medicine (STRIME) (research group)
- BioMS (research group)
- Infection Medicine Proteomics (research group)
- LTH Profile Area: Engineering Health
- Department of Immunotechnology
- Immunomodulatory effects of platelets during inflammation and infection (research group)
- Experimental Infection Medicine, Malmö (research group)
- Center of Pediatric Rheumatology (research group)
- LU-ATMP: Lund University Advanced Therapy Medicinal Products
- LUCC: Lund University Cancer Centre
- SEBRA Sepsis and Bacterial Resistance Alliance (research group)
- LU Profile Area: Light and Materials
- LTH Profile Area: Nanoscience and Semiconductor Technology
- NanoLund: Centre for Nanoscience
- LTH Profile Area: Photon Science and Technology
- publishing date
- 2024-04-15
- 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}}, }