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A human monoclonal antibody bivalently binding two different epitopes in streptococcal M protein mediates immune function

Bahnan, Wael LU ; Happonen, Lotta LU ; Khakzad, Hamed ; Kumra Ahnlide, Vibha LU ; de Neergaard, Therese LU ; Wrighton, Sebastian LU orcid ; André, Oscar LU ; Bratanis, Eleni LU ; Tang, Di LU orcid and Hellmark, Thomas LU orcid , et al. (2023) In EMBO Molecular Medicine 15(2). p.1-21
Abstract

Group A streptococci have evolved multiple strategies to evade human antibodies, making it challenging to create effective vaccines or antibody treatments. Here, we have generated antibodies derived from the memory B cells of an individual who had successfully cleared a group A streptococcal infection. The antibodies bind with high affinity in the central region of the surface-bound M protein. Such antibodies are typically non-opsonic. However, one antibody could effectively promote vital immune functions, including phagocytosis and in vivo protection. Remarkably, this antibody primarily interacts through a bivalent dual-Fab cis mode, where the Fabs bind to two distinct epitopes in the M protein. The dual-Fab cis-binding phenomenon is... (More)

Group A streptococci have evolved multiple strategies to evade human antibodies, making it challenging to create effective vaccines or antibody treatments. Here, we have generated antibodies derived from the memory B cells of an individual who had successfully cleared a group A streptococcal infection. The antibodies bind with high affinity in the central region of the surface-bound M protein. Such antibodies are typically non-opsonic. However, one antibody could effectively promote vital immune functions, including phagocytosis and in vivo protection. Remarkably, this antibody primarily interacts through a bivalent dual-Fab cis mode, where the Fabs bind to two distinct epitopes in the M protein. The dual-Fab cis-binding phenomenon is conserved across different groups of M types. In contrast, other antibodies binding with normal single-Fab mode to the same region cannot bypass the M protein's virulent effects. A broadly binding, protective monoclonal antibody could be a candidate for anti-streptococcal therapy. Our findings highlight the concept of dual-Fab cis binding as a means to access conserved, and normally non-opsonic regions, regions for protective antibody targeting.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
EMBO Molecular Medicine
volume
15
issue
2
pages
1 - 21
publisher
Wiley-Blackwell
external identifiers
  • scopus:85143836581
  • pmid:36507602
ISSN
1757-4684
DOI
10.15252/emmm.202216208
language
English
LU publication?
yes
additional info
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
id
19c5ce3d-8c88-431d-9380-05164456031b
date added to LUP
2022-12-14 10:42:34
date last changed
2024-04-14 04:55:14
@article{19c5ce3d-8c88-431d-9380-05164456031b,
  abstract     = {{<p>Group A streptococci have evolved multiple strategies to evade human antibodies, making it challenging to create effective vaccines or antibody treatments. Here, we have generated antibodies derived from the memory B cells of an individual who had successfully cleared a group A streptococcal infection. The antibodies bind with high affinity in the central region of the surface-bound M protein. Such antibodies are typically non-opsonic. However, one antibody could effectively promote vital immune functions, including phagocytosis and in vivo protection. Remarkably, this antibody primarily interacts through a bivalent dual-Fab cis mode, where the Fabs bind to two distinct epitopes in the M protein. The dual-Fab cis-binding phenomenon is conserved across different groups of M types. In contrast, other antibodies binding with normal single-Fab mode to the same region cannot bypass the M protein's virulent effects. A broadly binding, protective monoclonal antibody could be a candidate for anti-streptococcal therapy. Our findings highlight the concept of dual-Fab cis binding as a means to access conserved, and normally non-opsonic regions, regions for protective antibody targeting.</p>}},
  author       = {{Bahnan, Wael and Happonen, Lotta and Khakzad, Hamed and Kumra Ahnlide, Vibha and de Neergaard, Therese and Wrighton, Sebastian and André, Oscar and Bratanis, Eleni and Tang, Di and Hellmark, Thomas and Björck, Lars and Shannon, Oonagh and Malmström, Lars and Malmström, Johan and Nordenfelt, Pontus}},
  issn         = {{1757-4684}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{1--21}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{EMBO Molecular Medicine}},
  title        = {{A human monoclonal antibody bivalently binding two different epitopes in streptococcal M protein mediates immune function}},
  url          = {{http://dx.doi.org/10.15252/emmm.202216208}},
  doi          = {{10.15252/emmm.202216208}},
  volume       = {{15}},
  year         = {{2023}},
}