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Subclass-switched anti-Spike IgG3 oligoclonal cocktails strongly enhance Fc-mediated opsonization

Izadi, Arman LU ; Hailu, Arsema LU ; Godzwon, Magdalena LU ; Wrighton, Sebastian LU orcid ; Olofsson, Berit LU orcid ; Schmidt, Tobias LU ; Söderlund Strand, Anna LU ; Elder, Elizabeth ; Appelberg, Sofia and Valsjö, Maria , et al. (2023) In Proceedings of the National Academy of Sciences 120(15).
Abstract
Antibodies play a central role in the immune defense against SARS-CoV-2. Emerging evidence has shown that nonneutralizing antibodies are important for immune defense through Fc-mediated effector functions. Antibody subclass is known to affect downstream Fc function. However, whether the antibody subclass plays a role in anti-SARS-CoV-2 immunity remains unclear. Here, we subclass-switched eight human IgG1 anti-spike monoclonal antibodies (mAbs) to the IgG3 subclass by exchanging their constant domains. The IgG3 mAbs exhibited altered avidities to the spike protein and more potent Fc-mediated phagocytosis and complement activation than their IgG1 counterparts. Moreover, combining mAbs into oligoclonal cocktails led to enhanced Fc- and... (More)
Antibodies play a central role in the immune defense against SARS-CoV-2. Emerging evidence has shown that nonneutralizing antibodies are important for immune defense through Fc-mediated effector functions. Antibody subclass is known to affect downstream Fc function. However, whether the antibody subclass plays a role in anti-SARS-CoV-2 immunity remains unclear. Here, we subclass-switched eight human IgG1 anti-spike monoclonal antibodies (mAbs) to the IgG3 subclass by exchanging their constant domains. The IgG3 mAbs exhibited altered avidities to the spike protein and more potent Fc-mediated phagocytosis and complement activation than their IgG1 counterparts. Moreover, combining mAbs into oligoclonal cocktails led to enhanced Fc- and complement receptor-mediated phagocytosis, superior to even the most potent single IgG3 mAb when compared at equivalent concentrations. Finally, in an in vivo model, we show that opsonic mAbs of both subclasses can be protective against a SARS-CoV-2 infection, despite the antibodies being nonneutralizing. Our results suggest that opsonic IgG3 oligoclonal cocktails are a promising idea to explore for therapy against SARS-CoV-2, its emerging variants, and potentially other viruses. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antikroppar, SARS-COV-2, Fagocytos, Neutrofiler, COVID-19
in
Proceedings of the National Academy of Sciences
volume
120
issue
15
publisher
National Academy of Sciences
external identifiers
  • pmid:37011197
  • scopus:85151658285
ISSN
1091-6490
DOI
10.1073/pnas.2217590120
project
Functional Impact of Immunoglobulin G subclass in Bacterial and viral Infections
language
English
LU publication?
yes
id
8990ecff-de85-4af9-a531-8eae11915524
date added to LUP
2023-04-03 22:41:33
date last changed
2024-05-16 09:18:40
@article{8990ecff-de85-4af9-a531-8eae11915524,
  abstract     = {{Antibodies play a central role in the immune defense against SARS-CoV-2. Emerging evidence has shown that nonneutralizing antibodies are important for immune defense through Fc-mediated effector functions. Antibody subclass is known to affect downstream Fc function. However, whether the antibody subclass plays a role in anti-SARS-CoV-2 immunity remains unclear. Here, we subclass-switched eight human IgG1 anti-spike monoclonal antibodies (mAbs) to the IgG3 subclass by exchanging their constant domains. The IgG3 mAbs exhibited altered avidities to the spike protein and more potent Fc-mediated phagocytosis and complement activation than their IgG1 counterparts. Moreover, combining mAbs into oligoclonal cocktails led to enhanced Fc- and complement receptor-mediated phagocytosis, superior to even the most potent single IgG3 mAb when compared at equivalent concentrations. Finally, in an in vivo model, we show that opsonic mAbs of both subclasses can be protective against a SARS-CoV-2 infection, despite the antibodies being nonneutralizing. Our results suggest that opsonic IgG3 oligoclonal cocktails are a promising idea to explore for therapy against SARS-CoV-2, its emerging variants, and potentially other viruses.}},
  author       = {{Izadi, Arman and Hailu, Arsema and Godzwon, Magdalena and Wrighton, Sebastian and Olofsson, Berit and Schmidt, Tobias and Söderlund Strand, Anna and Elder, Elizabeth and Appelberg, Sofia and Valsjö, Maria and Larsson, Olivia and Wendel-Hansen, Vidar and Ohlin, Mats and Bahnan, Wael and Nordenfelt, Pontus}},
  issn         = {{1091-6490}},
  keywords     = {{Antikroppar; SARS-COV-2; Fagocytos; Neutrofiler; COVID-19}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{15}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences}},
  title        = {{Subclass-switched anti-Spike IgG3 oligoclonal cocktails strongly enhance Fc-mediated opsonization}},
  url          = {{http://dx.doi.org/10.1073/pnas.2217590120}},
  doi          = {{10.1073/pnas.2217590120}},
  volume       = {{120}},
  year         = {{2023}},
}