Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies [electronic resource]
Bacterial Toxin; Crystal Structure; Epitope Mapping; Monoclonal Antibody; Nuclear Magnetic Resonance (Nmr); Seb; Staphylococcal Enterotoxin B; X-Ray Crystallography.
Saved in:
| Online Access: |
Online Access (via OSTI) |
|---|---|
| Format: | Government Document Electronic eBook |
| Language: | English |
| Published: |
Washington, D.C. : Oak Ridge, Tenn. :
United States. Department of Energy. Office of Basic Energy Sciences ; distributed by the Office of Scientific and Technical Information, U.S. Department of Energy,
2015.
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| Subjects: |
MARC
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| 245 | 0 | 0 | |a Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies |h [electronic resource] |
| 260 | |a Washington, D.C. : |b United States. Department of Energy. Office of Basic Energy Sciences ; |a Oak Ridge, Tenn. : |b distributed by the Office of Scientific and Technical Information, U.S. Department of Energy, |c 2015. | ||
| 300 | |a p. 6715-6730 : |b digital, PDF file. | ||
| 336 | |a text |b txt |2 rdacontent. | ||
| 337 | |a computer |b c |2 rdamedia. | ||
| 338 | |a online resource |b cr |2 rdacarrier. | ||
| 500 | |a Published through SciTech Connect. | ||
| 500 | |a 01/08/2015. | ||
| 500 | |a Journal of Biological Chemistry 290 11 ISSN 0021-9258 AM. | ||
| 500 | |a Kaushik Dutta; Avanish K. Varshney; Matthew C. Franklin; Michael Goger; Xiaobo Wang; Bettina C. Fries. | ||
| 500 | |a New York Structural Biology Center, New York, NY (United States) | ||
| 520 | 3 | |a 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. | |
| 520 | 0 | |a Bacterial Toxin; Crystal Structure; Epitope Mapping; Monoclonal Antibody; Nuclear Magnetic Resonance (Nmr); Seb; Staphylococcal Enterotoxin B; X-Ray Crystallography. | |
| 536 | |b AC02-98CH10886. | ||
| 650 | 7 | |a Basic Biological Sciences. |2 edbsc. | |
| 650 | 7 | |a Applied Life Sciences. |2 edbsc. | |
| 710 | 1 | |a United States. |b Department of Energy. |b Office of Basic Energy Sciences. |4 spn. | |
| 710 | 2 | |a National Institutes of Health (U.S.). |4 spn. | |
| 710 | 1 | |a United States. |b Department of Defense. |4 spn. | |
| 710 | 1 | |a United States. |b Department of Energy. |b Office of Scientific and Technical Information. |4 dst. | |
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