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

Arman Izadi, Yasaman Karami, Eleni Bratanis, Sebastian Wrighton, Hamed Khakzad, Maria Nyblom, Berit Olofsson, Lotta Happonen, Di Tang, Martin Sundwall, Magdalena Godzwon, Yashuan Chao, Alejandro Gomez Toledo, Tobias Schmidt, Mats Ohlin, Michael Nilges, Johan Malmström, Wael Bahnan, Oonagh Shannon, Lars Malmström and Pontus Nordenfelt ()
Additional contact information
Arman Izadi: Lund University
Yasaman Karami: CNRS, Inria, LORIA
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
Lars Malmström: Lund University
Pontus Nordenfelt: Lund University

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47928-8

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