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Title: Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies

Abstract

Staphylococcal enterotoxin B (SEB) is a superantigen that cross-links the major histocompatibility complex class II and specific V-β chains of the T-cell receptor, thus forming a ternary complex. Developing neutralizing mAb to disrupt the ternary complex and abrogate the resulting toxicity is a major therapeutic challenge because SEB is effective at very low concentrations. We show that combining two SEB-specific mAbs enhances their efficacy, even though one of the two mAbs by itself has no effect on neutralization. Crystallography was employed for fine-mapping conformational epitopes in binary and ternary complexes between SEB and Fab fragments. NMR spectroscopy was used to validate and identify subtle allosteric changes induced by mAbs binding to SEB. The mapping of epitopes established that a combination of different mAbs can enhance efficacy of mAb-mediated protection from SEB induced lethal shock by two different mechanisms: one mAb mixture promoted clearance of the toxin both in vitro and in vivo by FcR-mediated cross-linking and clearance, whereas the other mAb mixture induced subtle allosteric conformational changes in SEB that perturbed formation of the SEB·T-cell receptor·major histocompatibility complex class II trimer. Lastly structural information accurately predicted mAb binding to other superantigens that share conformational epitopes with SEB. Fine mapping ofmore » conformational epitopes is a powerful tool to establish the mechanism and optimize the action of synergistic mAb combinations.« less

Authors:
 [1];  [2];  [1];  [1];  [3];  [2]
  1. New York Structural Biology Center, New York, NY (United States)
  2. Stony Brook Univ., Stony Brook, NY (United States); Albert Einstein College of Medicine, Bronx, NY (United States)
  3. Albert Einstein College of Medicine, Bronx, NY (United States)
Publication Date:
Research Org.:
New York Structural Biology Center, New York, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); Department of Defense (DoD)
OSTI Identifier:
1347990
Grant/Contract Number:  
AC02-98CH10886
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 11; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; bacterial toxin; crystal structure; epitope mapping; monoclonal antibody; nuclear magnetic resonance (NMR); SEB; Staphylococcal enterotoxin B; X-ray crystallography

Citation Formats

Dutta, Kaushik, Varshney, Avanish K., Franklin, Matthew C., Goger, Michael, Wang, Xiaobo, and Fries, Bettina C. Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies. United States: N. p., 2015. Web. doi:10.1074/jbc.m114.630715.
Dutta, Kaushik, Varshney, Avanish K., Franklin, Matthew C., Goger, Michael, Wang, Xiaobo, & Fries, Bettina C. Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies. United States. doi:10.1074/jbc.m114.630715.
Dutta, Kaushik, Varshney, Avanish K., Franklin, Matthew C., Goger, Michael, Wang, Xiaobo, and Fries, Bettina C. Thu . "Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies". United States. doi:10.1074/jbc.m114.630715. https://www.osti.gov/servlets/purl/1347990.
@article{osti_1347990,
title = {Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies},
author = {Dutta, Kaushik and Varshney, Avanish K. and Franklin, Matthew C. and Goger, Michael and Wang, Xiaobo and Fries, Bettina C.},
abstractNote = {Staphylococcal enterotoxin B (SEB) is a superantigen that cross-links the major histocompatibility complex class II and specific V-β chains of the T-cell receptor, thus forming a ternary complex. Developing neutralizing mAb to disrupt the ternary complex and abrogate the resulting toxicity is a major therapeutic challenge because SEB is effective at very low concentrations. We show that combining two SEB-specific mAbs enhances their efficacy, even though one of the two mAbs by itself has no effect on neutralization. Crystallography was employed for fine-mapping conformational epitopes in binary and ternary complexes between SEB and Fab fragments. NMR spectroscopy was used to validate and identify subtle allosteric changes induced by mAbs binding to SEB. The mapping of epitopes established that a combination of different mAbs can enhance efficacy of mAb-mediated protection from SEB induced lethal shock by two different mechanisms: one mAb mixture promoted clearance of the toxin both in vitro and in vivo by FcR-mediated cross-linking and clearance, whereas the other mAb mixture induced subtle allosteric conformational changes in SEB that perturbed formation of the SEB·T-cell receptor·major histocompatibility complex class II trimer. Lastly structural information accurately predicted mAb binding to other superantigens that share conformational epitopes with SEB. Fine mapping of conformational epitopes is a powerful tool to establish the mechanism and optimize the action of synergistic mAb combinations.},
doi = {10.1074/jbc.m114.630715},
journal = {Journal of Biological Chemistry},
number = 11,
volume = 290,
place = {United States},
year = {2015},
month = {1}
}

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