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Therapeutic Treatment of Aerosolized Staphylococcal Enterotoxin B in Nonhuman Primates with two Monoclonal Antibodies

Daniel Verreault, Jane Ennis, Kevin Whaley, Stephanie Z. Killeen, Hatice Karauzum, M.Javad Aman, Rick Holtsberg, Lara Doyle-Meyers, Peter J. Didier, Larry Zeitlin, View ORCID ProfileChad J. Roy
doi: https://doi.org/10.1101/424036
Daniel Verreault
1Divisions of Microbiology, Veterinary Medicine, and Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433
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Jane Ennis
2Mapp Biopharmaceutical, San Diego, CA 92121
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Kevin Whaley
2Mapp Biopharmaceutical, San Diego, CA 92121
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Stephanie Z. Killeen
1Divisions of Microbiology, Veterinary Medicine, and Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433
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Hatice Karauzum
3Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878
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M.Javad Aman
3Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878
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Rick Holtsberg
3Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878
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Lara Doyle-Meyers
1Divisions of Microbiology, Veterinary Medicine, and Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433
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Peter J. Didier
1Divisions of Microbiology, Veterinary Medicine, and Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433
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Larry Zeitlin
2Mapp Biopharmaceutical, San Diego, CA 92121
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Chad J. Roy
1Divisions of Microbiology, Veterinary Medicine, and Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433
4Department of Microbiology and Immunology, Tulane School of Medicine, New Orleans, LA 70112
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  • ORCID record for Chad J. Roy
  • For correspondence: croy@tulane.edu
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Abstract

Staphylococcal enterotoxin B (SEB) is a protein exotoxin found on the cell surface of Staphylococcus aureus that is the source for multiple pathologies in man. When purified and concentrated in aerosol form, SEB can cause an acute and often fatal intoxication, and thus is considered a biological threat agent. There are currently no vaccines or treatments approved for human use. Studies in rodent models of SEB intoxication show that antibody therapy may be a promising treatment strategy, however many have used antibodies only prophylactically or well before any clinical signs of intoxication are apparent. We assessed and compared the protective efficacy of two monoclonal antibodies, Ig121 and c19F1, when administered after aerosol exposure in a uniformly lethal nonhuman primate model of SEB intoxication. Rhesus macaques were challenged using small particle aerosols of SEB, and then were infused intravenously with a single dose of either Ig121 or c19F1 (10 mg/kg) at either 0.5, 2 or 4 hours postexposure. Onset of clinical signs, hematological, and cytokine response in untreated controls confirmed the acute onset and potency of the toxin used in the challenge. All animals administered either Ig121 or c19F1 survived SEB challenge, whereas the untreated controls succumbed to SEB intoxication 30-48 hours postexposure. These results represent the successful therapeutic in vivo protection by two investigational drugs against SEB in a severe nonhuman primate disease model and punctuate the therapeutic value of monoclonal antibodies hold when faced with treatment options for SEB-induced toxicity in a postexposure setting.

One Sentence Summary: Two high-affinity monoclonal antibodies were tested for therapeutic efficacy using a rhesus macaque challenge model of aerosolized SEB

Abbreviations used

ALT
alanine aminotransferase
APCs
antigen presenting cells
AST
aspartate aminotransferase
AAALAC
Association for the Assessment and Accreditation of Laboratory Animal Care International
BUN
blood urea nitrogen
CDC
Centers for Disease Prevention and Control
ED50
effective dose 50%
ELISA
enzyme linked immunosorbent assay
G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte macrophage colony stimulating factor
HRP
horseradish perioxidase
IL-18
interleukin 18
IL-17
interleukin 17
IL-15
interleukin 15
IL-13
interleukin 13
IL-12/23
interleukin12/23
IL-10
interleukin 10
IL-8
interleukin 8
IL-6
interleukin 6
IL-5
interleukin 5
IL-4
interleukin 4
IL-2
interleukin 2
IL-1β
interleukin 1 beta
IL-1ra
interleukin 1 receptor antagonist
IM
intramuscular
IV
intravenous
IFN-γ
interferon gamma
LD50
lethal dose 50%
LPS
lipopolysaccharide
MHC
major histocompatibility complex
MIP-1β
macrophage inflammatory protein-1 beta
MIP-1α
macrophage inflammatory protein-1 alpha
MCP-1
monocyte chemoattractant protein-1
NIH
National Institutes of Health
SIV
simian immunodeficiency virus
sCD40L
soluble CD40-ligand
SEB
staphylococcal enterotoxin B
SAgs
superantigens
TCR
T cell receptor
TSS
toxic shock syndrome
TMB
3,3’,5,5’-Tetramethylbenzidine
TNPRC
Tulane National Primate Research Center
TNF-α
tumor necrosis factor-alpha
TGF-α
tumor granulocyte factor-alpha
VEGF
vascular endothelial growth factor
  • Abbreviations used

    ALT
    alanine aminotransferase
    APCs
    antigen presenting cells
    AST
    aspartate aminotransferase
    AAALAC
    Association for the Assessment and Accreditation of Laboratory Animal Care International
    BUN
    blood urea nitrogen
    CDC
    Centers for Disease Prevention and Control
    ED50
    effective dose 50%
    ELISA
    enzyme linked immunosorbent assay
    G-CSF
    granulocyte colony-stimulating factor
    GM-CSF
    granulocyte macrophage colony stimulating factor
    HRP
    horseradish perioxidase
    IL-18
    interleukin 18
    IL-17
    interleukin 17
    IL-15
    interleukin 15
    IL-13
    interleukin 13
    IL-12/23
    interleukin12/23
    IL-10
    interleukin 10
    IL-8
    interleukin 8
    IL-6
    interleukin 6
    IL-5
    interleukin 5
    IL-4
    interleukin 4
    IL-2
    interleukin 2
    IL-1β
    interleukin 1 beta
    IL-1ra
    interleukin 1 receptor antagonist
    IM
    intramuscular
    IV
    intravenous
    IFN-γ
    interferon gamma
    LD50
    lethal dose 50%
    LPS
    lipopolysaccharide
    MHC
    major histocompatibility complex
    MIP-1β
    macrophage inflammatory protein-1 beta
    MIP-1α
    macrophage inflammatory protein-1 alpha
    MCP-1
    monocyte chemoattractant protein-1
    NIH
    National Institutes of Health
    SIV
    simian immunodeficiency virus
    sCD40L
    soluble CD40-ligand
    SEB
    staphylococcal enterotoxin B
    SAgs
    superantigens
    TCR
    T cell receptor
    TSS
    toxic shock syndrome
    TMB
    3,3’,5,5’-Tetramethylbenzidine
    TNPRC
    Tulane National Primate Research Center
    TNF-α
    tumor necrosis factor-alpha
    TGF-α
    tumor granulocyte factor-alpha
    VEGF
    vascular endothelial growth factor
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted September 23, 2018.
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    Therapeutic Treatment of Aerosolized Staphylococcal Enterotoxin B in Nonhuman Primates with two Monoclonal Antibodies
    Daniel Verreault, Jane Ennis, Kevin Whaley, Stephanie Z. Killeen, Hatice Karauzum, M.Javad Aman, Rick Holtsberg, Lara Doyle-Meyers, Peter J. Didier, Larry Zeitlin, Chad J. Roy
    bioRxiv 424036; doi: https://doi.org/10.1101/424036
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    Therapeutic Treatment of Aerosolized Staphylococcal Enterotoxin B in Nonhuman Primates with two Monoclonal Antibodies
    Daniel Verreault, Jane Ennis, Kevin Whaley, Stephanie Z. Killeen, Hatice Karauzum, M.Javad Aman, Rick Holtsberg, Lara Doyle-Meyers, Peter J. Didier, Larry Zeitlin, Chad J. Roy
    bioRxiv 424036; doi: https://doi.org/10.1101/424036

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