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Clinical Trial
. 2024 Dec 31;20(1):2360338.
doi: 10.1080/21645515.2024.2360338. Epub 2024 Jun 10.

A highly neutralizing human monoclonal antibody targeting a novel linear epitope on staphylococcal enterotoxin B

Hongyin Fan  1 , Liqun Zhao  1 , Weiwei Wang  2 , Feng Yu  2 , Haiming Jing  1 , Yun Yang  1 , Xiaoli Zhang  3 , Zhuo Zhao  1 , Qiang Gou  1 , Weijun Zhang  1 , Quanming Zou  1 , Jinyong Zhang  1 , Hao Zeng  1   4
Affiliations
Clinical Trial

A highly neutralizing human monoclonal antibody targeting a novel linear epitope on staphylococcal enterotoxin B

Hongyin Fan et al. Hum Vaccin Immunother. .

Abstract

Staphylococcal Enterotoxin B (SEB), produced by Staphylococcus aureus (S. aureus), is a powerful superantigen that induces severe immune disruption and toxic shock syndrome (TSS) upon binding to MHC-II and TCR. Despite its significant impact on the pathogenesis of S. aureus, there are currently no specific therapeutic interventions available to counteract the mechanism of action exerted by this toxin. In this study, we have identified a human monoclonal antibody, named Hm0487, that specifically targets SEB by single-cell sequencing using PBMCs isolated from volunteers enrolled in a phase I clinical trial of the five-antigen S. aureus vaccine. X-ray crystallography studies revealed that Hm0487 exhibits high affinity for a linear B cell epitope in SEB (SEB138-147), which is located distantly from the site involved in the formation of the MHC-SEB-TCR ternary complex. Furthermore, in vitro studies demonstrated that Hm0487 significantly impacts the interaction of SEB with both receptors and the binding to immune cells, probably due to an allosteric effect on SEB rather than competing with receptors for binding sites. Moreover, both in vitro and in vivo studies validated that Hm0487 displayed efficient neutralizing efficacy in models of lethal shock and sepsis induced by either SEB or bacterial challenge. Our findings unveil an alternative mechanism for neutralizing the pathogenesis of SEB by Hm0487, and this antibody provides a novel strategy for mitigating both SEB-induced toxicity and S. aureus infection.

Keywords: Staphylococcus aureus; enterotoxin B; monoclonal antibody; neutralizing activity; structure.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1.
Figure 1.
Hm0487 binds SEB with high affinity.
Figure 2.
Figure 2.
Hm0487 recognizes a novel liner epitope in SEB.
Figure 3.
Figure 3.
SEB interacts with TCR, MHC-II and Hm0487 through distinct domains.
Figure 4.
Figure 4.
Hm0487 impact the binding of SEB with target cells.
Figure 5.
Figure 5.
Hm0487 protect mice from lethal SEB challenge.
Figure 6.
Figure 6.
Hm0487 protect against S. aureus-induced sepsis.
See this image and copyright information in PMC

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