RT Journal Article
SR Electronic
T1 Therapeutic Treatment of Aerosolized Staphylococcal Enterotoxin B in Nonhuman Primates with two Monoclonal Antibodies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 424036
DO 10.1101/424036
A1 Daniel Verreault
A1 Jane Ennis
A1 Kevin Whaley
A1 Stephanie Z. Killeen
A1 Hatice Karauzum
A1 M.Javad Aman
A1 Rick Holtsberg
A1 Lara Doyle-Meyers
A1 Peter J. Didier
A1 Larry Zeitlin
A1 Chad J. Roy
YR 2018
UL http://biorxiv.org/content/early/2018/09/23/424036.abstract
AB 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 SEBALTalanine aminotransferaseAPCsantigen presenting cellsASTaspartate aminotransferaseAAALACAssociation for the Assessment and Accreditation of Laboratory Animal Care InternationalBUNblood urea nitrogenCDCCenters for Disease Prevention and ControlED50effective dose 50%ELISAenzyme linked immunosorbent assayG-CSFgranulocyte colony-stimulating factorGM-CSFgranulocyte macrophage colony stimulating factorHRPhorseradish perioxidaseIL-18interleukin 18IL-17interleukin 17IL-15interleukin 15IL-13interleukin 13IL-12/23interleukin12/23IL-10interleukin 10IL-8interleukin 8IL-6interleukin 6IL-5interleukin 5IL-4interleukin 4IL-2interleukin 2IL-1βinterleukin 1 betaIL-1rainterleukin 1 receptor antagonistIMintramuscularIVintravenousIFN-γinterferon gammaLD50lethal dose 50%LPSlipopolysaccharideMHCmajor histocompatibility complexMIP-1βmacrophage inflammatory protein-1 betaMIP-1αmacrophage inflammatory protein-1 alphaMCP-1monocyte chemoattractant protein-1NIHNational Institutes of HealthSIVsimian immunodeficiency virussCD40Lsoluble CD40-ligandSEBstaphylococcal enterotoxin BSAgssuperantigensTCRT cell receptorTSStoxic shock syndromeTMB3,3’,5,5’-TetramethylbenzidineTNPRCTulane National Primate Research CenterTNF-αtumor necrosis factor-alphaTGF-αtumor granulocyte factor-alphaVEGFvascular endothelial growth factorALTalanine aminotransferaseAPCsantigen presenting cellsASTaspartate aminotransferaseAAALACAssociation for the Assessment and Accreditation of Laboratory Animal Care InternationalBUNblood urea nitrogenCDCCenters for Disease Prevention and ControlED50effective dose 50%ELISAenzyme linked immunosorbent assayG-CSFgranulocyte colony-stimulating factorGM-CSFgranulocyte macrophage colony stimulating factorHRPhorseradish perioxidaseIL-18interleukin 18IL-17interleukin 17IL-15interleukin 15IL-13interleukin 13IL-12/23interleukin12/23IL-10interleukin 10IL-8interleukin 8IL-6interleukin 6IL-5interleukin 5IL-4interleukin 4IL-2interleukin 2IL-1βinterleukin 1 betaIL-1rainterleukin 1 receptor antagonistIMintramuscularIVintravenousIFN-γinterferon gammaLD50lethal dose 50%LPSlipopolysaccharideMHCmajor histocompatibility complexMIP-1βmacrophage inflammatory protein-1 betaMIP-1αmacrophage inflammatory protein-1 alphaMCP-1monocyte chemoattractant protein-1NIHNational Institutes of HealthSIVsimian immunodeficiency virussCD40Lsoluble CD40-ligandSEBstaphylococcal enterotoxin BSAgssuperantigensTCRT cell receptorTSStoxic shock syndromeTMB3,3’,5,5’-TetramethylbenzidineTNPRCTulane National Primate Research CenterTNF-αtumor necrosis factor-alphaTGF-αtumor granulocyte factor-alphaVEGFvascular endothelial growth factor