Potent neutralization of staphylococcal enterotoxin b by synergistic action of chimeric antibodies

Mulualem E. Tilahun, Govindarajan Rajagopalan, Nalini Shah-Mahoney, Rebecca G. Lawlor, Ashenafi Y. Tilahun, Chen Xie, Kannan Natarajan, David H. Margulies, David I. Ratner, Barbara A. Osborne, Richard A. Goldsby

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Staphylococcal enterotoxin B (SEB), a shock-inducing exotoxin synthesized by Staphylococcus aureus, is an important cause of food poisoning and is a class B bioterrorism agent. SEB mediates antigen-independent activation of a major subset of the T-cell population by cross-linking T-cell receptors (TCRs) with class II major histocompatibility complex (MHC-II) molecules of antigen-presenting cells, resulting in the induction of antigen independent proliferation and cytokine secretion by a significant fraction of the T-cell population. Neutralizing antibodies inhibit SEB-mediated T-cell activation by blocking the toxin's interaction with the TCR or MHC-II and provide protection against the debilitating effects of this superantigen. We derived and searched a set of monoclonal mouse anti-SEB antibodies to identify neutralizing anti-SEB antibodies that bind to different sites on the toxin. A pair of non-cross-reactive, neutralizing anti-SEB monoclonal antibodies (MAbs) was found, and a combination of these antibodies inhibited SEB-induced T-cell proliferation in a synergistic rather than merely additive manner. In order to engineer antibodies more suitable than mouse MAbs for use in humans, the genes encoding the VL and VH gene segments of a synergistically acting pair of mouse MAbs were grafted, respectively, onto genes encoding the constant regions of human Igκ and human IgG1, transfected into mammalian cells, and used to generate chimeric versions of these antibodies that had affinity and neutralization profiles essentially identical to their mouse counterparts. When tested in cultures of human peripheral blood mononuclear cells or splenocytes derived from HLA-DR3 transgenic mice, the chimeric human-mouse antibodies synergistically neutralized SEB-induced T-cell activation and cytokine production.

Original languageEnglish (US)
Pages (from-to)2801-2811
Number of pages11
JournalInfection and Immunity
Volume78
Issue number6
DOIs
StatePublished - Jun 2010

Fingerprint

Enterotoxins
Antibodies
T-Lymphocytes
Monoclonal Antibodies
T-Cell Antigen Receptor
Major Histocompatibility Complex
Immunoglobulin Constant Regions
Biological Warfare Agents
HLA-DR3 Antigen
Cytokines
Genes
Antigens
Exotoxins
Superantigens
Foodborne Diseases
Antibody Affinity
staphylococcal enterotoxin B
T-Lymphocyte Subsets
Antigen-Presenting Cells
Neutralizing Antibodies

ASJC Scopus subject areas

  • Immunology
  • Microbiology
  • Parasitology
  • Infectious Diseases

Cite this

Tilahun, M. E., Rajagopalan, G., Shah-Mahoney, N., Lawlor, R. G., Tilahun, A. Y., Xie, C., ... Goldsby, R. A. (2010). Potent neutralization of staphylococcal enterotoxin b by synergistic action of chimeric antibodies. Infection and Immunity, 78(6), 2801-2811. https://doi.org/10.1128/IAI.01121-09

Potent neutralization of staphylococcal enterotoxin b by synergistic action of chimeric antibodies. / Tilahun, Mulualem E.; Rajagopalan, Govindarajan; Shah-Mahoney, Nalini; Lawlor, Rebecca G.; Tilahun, Ashenafi Y.; Xie, Chen; Natarajan, Kannan; Margulies, David H.; Ratner, David I.; Osborne, Barbara A.; Goldsby, Richard A.

In: Infection and Immunity, Vol. 78, No. 6, 06.2010, p. 2801-2811.

Research output: Contribution to journalArticle

Tilahun, ME, Rajagopalan, G, Shah-Mahoney, N, Lawlor, RG, Tilahun, AY, Xie, C, Natarajan, K, Margulies, DH, Ratner, DI, Osborne, BA & Goldsby, RA 2010, 'Potent neutralization of staphylococcal enterotoxin b by synergistic action of chimeric antibodies', Infection and Immunity, vol. 78, no. 6, pp. 2801-2811. https://doi.org/10.1128/IAI.01121-09
Tilahun ME, Rajagopalan G, Shah-Mahoney N, Lawlor RG, Tilahun AY, Xie C et al. Potent neutralization of staphylococcal enterotoxin b by synergistic action of chimeric antibodies. Infection and Immunity. 2010 Jun;78(6):2801-2811. https://doi.org/10.1128/IAI.01121-09
Tilahun, Mulualem E. ; Rajagopalan, Govindarajan ; Shah-Mahoney, Nalini ; Lawlor, Rebecca G. ; Tilahun, Ashenafi Y. ; Xie, Chen ; Natarajan, Kannan ; Margulies, David H. ; Ratner, David I. ; Osborne, Barbara A. ; Goldsby, Richard A. / Potent neutralization of staphylococcal enterotoxin b by synergistic action of chimeric antibodies. In: Infection and Immunity. 2010 ; Vol. 78, No. 6. pp. 2801-2811.
@article{fed0fca8289c4ac7b40cd6c549395f8a,
title = "Potent neutralization of staphylococcal enterotoxin b by synergistic action of chimeric antibodies",
abstract = "Staphylococcal enterotoxin B (SEB), a shock-inducing exotoxin synthesized by Staphylococcus aureus, is an important cause of food poisoning and is a class B bioterrorism agent. SEB mediates antigen-independent activation of a major subset of the T-cell population by cross-linking T-cell receptors (TCRs) with class II major histocompatibility complex (MHC-II) molecules of antigen-presenting cells, resulting in the induction of antigen independent proliferation and cytokine secretion by a significant fraction of the T-cell population. Neutralizing antibodies inhibit SEB-mediated T-cell activation by blocking the toxin's interaction with the TCR or MHC-II and provide protection against the debilitating effects of this superantigen. We derived and searched a set of monoclonal mouse anti-SEB antibodies to identify neutralizing anti-SEB antibodies that bind to different sites on the toxin. A pair of non-cross-reactive, neutralizing anti-SEB monoclonal antibodies (MAbs) was found, and a combination of these antibodies inhibited SEB-induced T-cell proliferation in a synergistic rather than merely additive manner. In order to engineer antibodies more suitable than mouse MAbs for use in humans, the genes encoding the VL and VH gene segments of a synergistically acting pair of mouse MAbs were grafted, respectively, onto genes encoding the constant regions of human Igκ and human IgG1, transfected into mammalian cells, and used to generate chimeric versions of these antibodies that had affinity and neutralization profiles essentially identical to their mouse counterparts. When tested in cultures of human peripheral blood mononuclear cells or splenocytes derived from HLA-DR3 transgenic mice, the chimeric human-mouse antibodies synergistically neutralized SEB-induced T-cell activation and cytokine production.",
author = "Tilahun, {Mulualem E.} and Govindarajan Rajagopalan and Nalini Shah-Mahoney and Lawlor, {Rebecca G.} and Tilahun, {Ashenafi Y.} and Chen Xie and Kannan Natarajan and Margulies, {David H.} and Ratner, {David I.} and Osborne, {Barbara A.} and Goldsby, {Richard A.}",
year = "2010",
month = "6",
doi = "10.1128/IAI.01121-09",
language = "English (US)",
volume = "78",
pages = "2801--2811",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "6",

}

TY - JOUR

T1 - Potent neutralization of staphylococcal enterotoxin b by synergistic action of chimeric antibodies

AU - Tilahun, Mulualem E.

AU - Rajagopalan, Govindarajan

AU - Shah-Mahoney, Nalini

AU - Lawlor, Rebecca G.

AU - Tilahun, Ashenafi Y.

AU - Xie, Chen

AU - Natarajan, Kannan

AU - Margulies, David H.

AU - Ratner, David I.

AU - Osborne, Barbara A.

AU - Goldsby, Richard A.

PY - 2010/6

Y1 - 2010/6

N2 - Staphylococcal enterotoxin B (SEB), a shock-inducing exotoxin synthesized by Staphylococcus aureus, is an important cause of food poisoning and is a class B bioterrorism agent. SEB mediates antigen-independent activation of a major subset of the T-cell population by cross-linking T-cell receptors (TCRs) with class II major histocompatibility complex (MHC-II) molecules of antigen-presenting cells, resulting in the induction of antigen independent proliferation and cytokine secretion by a significant fraction of the T-cell population. Neutralizing antibodies inhibit SEB-mediated T-cell activation by blocking the toxin's interaction with the TCR or MHC-II and provide protection against the debilitating effects of this superantigen. We derived and searched a set of monoclonal mouse anti-SEB antibodies to identify neutralizing anti-SEB antibodies that bind to different sites on the toxin. A pair of non-cross-reactive, neutralizing anti-SEB monoclonal antibodies (MAbs) was found, and a combination of these antibodies inhibited SEB-induced T-cell proliferation in a synergistic rather than merely additive manner. In order to engineer antibodies more suitable than mouse MAbs for use in humans, the genes encoding the VL and VH gene segments of a synergistically acting pair of mouse MAbs were grafted, respectively, onto genes encoding the constant regions of human Igκ and human IgG1, transfected into mammalian cells, and used to generate chimeric versions of these antibodies that had affinity and neutralization profiles essentially identical to their mouse counterparts. When tested in cultures of human peripheral blood mononuclear cells or splenocytes derived from HLA-DR3 transgenic mice, the chimeric human-mouse antibodies synergistically neutralized SEB-induced T-cell activation and cytokine production.

AB - Staphylococcal enterotoxin B (SEB), a shock-inducing exotoxin synthesized by Staphylococcus aureus, is an important cause of food poisoning and is a class B bioterrorism agent. SEB mediates antigen-independent activation of a major subset of the T-cell population by cross-linking T-cell receptors (TCRs) with class II major histocompatibility complex (MHC-II) molecules of antigen-presenting cells, resulting in the induction of antigen independent proliferation and cytokine secretion by a significant fraction of the T-cell population. Neutralizing antibodies inhibit SEB-mediated T-cell activation by blocking the toxin's interaction with the TCR or MHC-II and provide protection against the debilitating effects of this superantigen. We derived and searched a set of monoclonal mouse anti-SEB antibodies to identify neutralizing anti-SEB antibodies that bind to different sites on the toxin. A pair of non-cross-reactive, neutralizing anti-SEB monoclonal antibodies (MAbs) was found, and a combination of these antibodies inhibited SEB-induced T-cell proliferation in a synergistic rather than merely additive manner. In order to engineer antibodies more suitable than mouse MAbs for use in humans, the genes encoding the VL and VH gene segments of a synergistically acting pair of mouse MAbs were grafted, respectively, onto genes encoding the constant regions of human Igκ and human IgG1, transfected into mammalian cells, and used to generate chimeric versions of these antibodies that had affinity and neutralization profiles essentially identical to their mouse counterparts. When tested in cultures of human peripheral blood mononuclear cells or splenocytes derived from HLA-DR3 transgenic mice, the chimeric human-mouse antibodies synergistically neutralized SEB-induced T-cell activation and cytokine production.

UR - http://www.scopus.com/inward/record.url?scp=77952718853&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952718853&partnerID=8YFLogxK

U2 - 10.1128/IAI.01121-09

DO - 10.1128/IAI.01121-09

M3 - Article

VL - 78

SP - 2801

EP - 2811

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 6

ER -