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Protective non-neutralizing mAbs targets conserved opsonic epitopes on SARS-CoV-2 variants

Izadi, Arman LU ; Godzwon, Magdalena LU ; Ohlin, Mats LU orcid and Nordenfelt, Pontus LU orcid (2023)
Abstract
Antibodies play a central role in the immune defense against SARS-CoV-2. Strong evidence has shown that non-neutralizing antibodies (nnAbs) are important for anti-SARS-Cov-2 immunity through Fc-mediated effector functions. These nnAbs bind to epitopes that could be less subjected to mutations in the emerging variants. When protective, such nnAbs would constitute a more promising alternative to neutralizing mAbs (nAbs). Here, we show that six nnAbs retain binding to Omicron, while two nAbs do not. Furthermore, two of our nnAbs, which are protective in vivo, retained binding to XBB, XBB.1.5, and BQ.1.1. They appear to bind to conserved epitopes on the N-terminal and receptor binding domain (RBD), respectively. As a proof of concept, we show... (More)
Antibodies play a central role in the immune defense against SARS-CoV-2. Strong evidence has shown that non-neutralizing antibodies (nnAbs) are important for anti-SARS-Cov-2 immunity through Fc-mediated effector functions. These nnAbs bind to epitopes that could be less subjected to mutations in the emerging variants. When protective, such nnAbs would constitute a more promising alternative to neutralizing mAbs (nAbs). Here, we show that six nnAbs retain binding to Omicron, while two nAbs do not. Furthermore, two of our nnAbs, which are protective in vivo, retained binding to XBB, XBB.1.5, and BQ.1.1. They appear to bind to conserved epitopes on the N-terminal and receptor binding domain (RBD), respectively. As a proof of concept, we show that these protective non-neutralizing antibodies retain potent Fc-mediated opsonic function against BQ.1.1 and XBB. We also show that the Fc-mediated function is further enhanced by expressing the antibodies in the IgG3 subclass and combining them into a dual antibody cocktail. Our work suggests that opsonizing nnAbs could be a viable strategy for anti-SARS-CoV-2 mAb therapies against current and future SARS-CoV-2 variants. (Less)
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author
; ; and
organization
publishing date
type
Working paper/Preprint
publication status
published
subject
publisher
bioRxiv
DOI
10.1101/2023.09.29.560084
language
English
LU publication?
yes
id
9a4c2144-f852-4ed3-9649-f24271d376c2
date added to LUP
2023-09-30 14:32:55
date last changed
2023-11-07 10:05:17
@misc{9a4c2144-f852-4ed3-9649-f24271d376c2,
  abstract     = {{Antibodies play a central role in the immune defense against SARS-CoV-2. Strong evidence has shown that non-neutralizing antibodies (nnAbs) are important for anti-SARS-Cov-2 immunity through Fc-mediated effector functions. These nnAbs bind to epitopes that could be less subjected to mutations in the emerging variants. When protective, such nnAbs would constitute a more promising alternative to neutralizing mAbs (nAbs). Here, we show that six nnAbs retain binding to Omicron, while two nAbs do not. Furthermore, two of our nnAbs, which are protective in vivo, retained binding to XBB, XBB.1.5, and BQ.1.1. They appear to bind to conserved epitopes on the N-terminal and receptor binding domain (RBD), respectively. As a proof of concept, we show that these protective non-neutralizing antibodies retain potent Fc-mediated opsonic function against BQ.1.1 and XBB. We also show that the Fc-mediated function is further enhanced by expressing the antibodies in the IgG3 subclass and combining them into a dual antibody cocktail. Our work suggests that opsonizing nnAbs could be a viable strategy for anti-SARS-CoV-2 mAb therapies against current and future SARS-CoV-2 variants.}},
  author       = {{Izadi, Arman and Godzwon, Magdalena and Ohlin, Mats and Nordenfelt, Pontus}},
  language     = {{eng}},
  month        = {{09}},
  note         = {{Preprint}},
  publisher    = {{bioRxiv}},
  title        = {{Protective non-neutralizing mAbs targets conserved opsonic epitopes on SARS-CoV-2 variants}},
  url          = {{http://dx.doi.org/10.1101/2023.09.29.560084}},
  doi          = {{10.1101/2023.09.29.560084}},
  year         = {{2023}},
}