tetano
Editor, Senior Moderator
Nat Commun
. 2024 Apr 27;15(1):3600.
doi: 10.1038/s41467-024-47928-8. The hinge-engineered IgG1-IgG3 hybrid subclass IgGh[SUB]47[/SUB] potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies
Arman Izadi[SUP] 1 [/SUP], Yasaman Karami[SUP] 2 3 [/SUP], Eleni Bratanis[SUP] 1 [/SUP], Sebastian Wrighton[SUP] 1 [/SUP], Hamed Khakzad[SUP] 2 [/SUP], Maria Nyblom[SUP] 4 [/SUP], Berit Olofsson[SUP] 1 [/SUP], Lotta Happonen[SUP] 1 [/SUP], Di Tang[SUP] 1 [/SUP], Martin Sundwall[SUP] 1 [/SUP], Magdalena Godzwon[SUP] 5 [/SUP], Yashuan Chao[SUP] 1 [/SUP], Alejandro Gomez Toledo[SUP] 1 [/SUP], Tobias Schmidt[SUP] 6 [/SUP], Mats Ohlin[SUP] 5 [/SUP], Michael Nilges[SUP] 3 [/SUP], Johan Malmström[SUP] 1 [/SUP], Wael Bahnan[SUP] 1 [/SUP], Oonagh Shannon[SUP] 1 7 [/SUP], Lars Malmström[SUP] 1 [/SUP], Pontus Nordenfelt[SUP] 8 9 [/SUP]
Affiliations
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[SUB]xx[/SUB]. 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[SUB]47[/SUB] shows improved protection against S. pyogenes in a systemic infection mouse model, suggesting that IgGh[SUB]47[/SUB] has promise as a preclinical therapeutic candidate. Importantly, the enhanced opsonic function of IgGh[SUB]47[/SUB] is generalizable to diverse S. pyogenes strains from clinical isolates. We generated IgGh[SUB]47[/SUB] 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[SUB]47[/SUB] subclass in two distant biological systems provides new insights into antibody function.
. 2024 Apr 27;15(1):3600.
doi: 10.1038/s41467-024-47928-8. The hinge-engineered IgG1-IgG3 hybrid subclass IgGh[SUB]47[/SUB] potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies
Arman Izadi[SUP] 1 [/SUP], Yasaman Karami[SUP] 2 3 [/SUP], Eleni Bratanis[SUP] 1 [/SUP], Sebastian Wrighton[SUP] 1 [/SUP], Hamed Khakzad[SUP] 2 [/SUP], Maria Nyblom[SUP] 4 [/SUP], Berit Olofsson[SUP] 1 [/SUP], Lotta Happonen[SUP] 1 [/SUP], Di Tang[SUP] 1 [/SUP], Martin Sundwall[SUP] 1 [/SUP], Magdalena Godzwon[SUP] 5 [/SUP], Yashuan Chao[SUP] 1 [/SUP], Alejandro Gomez Toledo[SUP] 1 [/SUP], Tobias Schmidt[SUP] 6 [/SUP], Mats Ohlin[SUP] 5 [/SUP], Michael Nilges[SUP] 3 [/SUP], Johan Malmström[SUP] 1 [/SUP], Wael Bahnan[SUP] 1 [/SUP], Oonagh Shannon[SUP] 1 7 [/SUP], Lars Malmström[SUP] 1 [/SUP], Pontus Nordenfelt[SUP] 8 9 [/SUP]
Affiliations
- PMID: 38678029
- PMCID: PMC11055898
- DOI: 10.1038/s41467-024-47928-8
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[SUB]xx[/SUB]. 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[SUB]47[/SUB] shows improved protection against S. pyogenes in a systemic infection mouse model, suggesting that IgGh[SUB]47[/SUB] has promise as a preclinical therapeutic candidate. Importantly, the enhanced opsonic function of IgGh[SUB]47[/SUB] is generalizable to diverse S. pyogenes strains from clinical isolates. We generated IgGh[SUB]47[/SUB] 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[SUB]47[/SUB] subclass in two distant biological systems provides new insights into antibody function.