TY - JOUR
T1 - Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin
AU - Roy, Chad J.
AU - Van Slyke, Greta
AU - Ehrbar, Dylan
AU - Bornholdt, Zachary A.
AU - Brennan, Miles B.
AU - Campbell, Lioudmila
AU - Chen, Michelle
AU - Kim, Do
AU - Mlakar, Neil
AU - Whaley, Kevin J.
AU - Froude, Jeffrey W.
AU - Torres-Velez, Fernando J.
AU - Vitetta, Ellen
AU - Didier, Peter J.
AU - Doyle-Meyers, Lara
AU - Zeitlin, Larry
AU - Mantis, Nicholas J.
N1 - Funding Information:
The authors thank the Wadsworth Center’s Biochemistry and Immunology core facility for assistance with flow cytometry and the Histopathology Core facility for assistance with tissue section preparations. We thank Dr. Javad Aman (Integrated BioTherapeutics) for the SEB MAb. This work was supported by Contract No. W911QY-16-C-0051 to LZ from the Department of the Army, Department of Defense, and Contract No. HHSN272201400021C and grant AI125190 to N.J.M. from the National Institutes of Allergy and Infectious Diseases, National Institutes of Health (NIH). The work at Tulane National Primate Research Center was also supported in part by grant OD011104 to C.J.R. from the Office of Research Infrastructure Programs (ORIP), Office of the Director, NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Defense or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Inhalation of ricin toxin (RT), a Category B biothreat agent, provokes an acute respiratory distress syndrome marked by pro-inflammatory cytokine and chemokine production, neutrophilic exudate, and pulmonary edema. The severity of RT exposure is attributed to the tropism of the toxin’s B subunit (RTB) for alveolar macrophages and airway epithelial cells, coupled with the extraordinarily potent ribosome-inactivating properties of the toxin’s enzymatic subunit (RTA). While there are currently no vaccines or treatments approved to prevent RT intoxication, we recently described a humanized anti-RTA IgG1 MAb, huPB10, that was able to rescue non-human primates (NHPs) from lethal dose RT aerosol challenge if administered by intravenous (IV) infusion within hours of toxin exposure. We have now engineered an extended serum half-life variant of that MAb, huPB10-LS, and evaluated it as a pre-exposure prophylactic. Five Rhesus macaques that received a single intravenous infusion (25 mg/kg) of huPB10-LS survived a lethal dose aerosol RT challenge 28 days later, whereas three control animals succumbed to RT intoxication within 48 h. The huPB10-LS treated animals remained clinically normal in the hours and days following toxin insult, suggesting that pre-existing antibody levels were sufficient to neutralize RT locally. Moreover, pro-inflammatory markers in sera and BAL fluids collected 24 h following RT challenge were significantly dampened in huPB10-LS treated animals, as compared to controls. Finally, we found that all five surviving animals, within days after RT exposure, had anti-RT serum IgG titers against epitopes other than huPB10-LS, indicative of active immunization by residual RT and/or RT-immune complexes.
AB - Inhalation of ricin toxin (RT), a Category B biothreat agent, provokes an acute respiratory distress syndrome marked by pro-inflammatory cytokine and chemokine production, neutrophilic exudate, and pulmonary edema. The severity of RT exposure is attributed to the tropism of the toxin’s B subunit (RTB) for alveolar macrophages and airway epithelial cells, coupled with the extraordinarily potent ribosome-inactivating properties of the toxin’s enzymatic subunit (RTA). While there are currently no vaccines or treatments approved to prevent RT intoxication, we recently described a humanized anti-RTA IgG1 MAb, huPB10, that was able to rescue non-human primates (NHPs) from lethal dose RT aerosol challenge if administered by intravenous (IV) infusion within hours of toxin exposure. We have now engineered an extended serum half-life variant of that MAb, huPB10-LS, and evaluated it as a pre-exposure prophylactic. Five Rhesus macaques that received a single intravenous infusion (25 mg/kg) of huPB10-LS survived a lethal dose aerosol RT challenge 28 days later, whereas three control animals succumbed to RT intoxication within 48 h. The huPB10-LS treated animals remained clinically normal in the hours and days following toxin insult, suggesting that pre-existing antibody levels were sufficient to neutralize RT locally. Moreover, pro-inflammatory markers in sera and BAL fluids collected 24 h following RT challenge were significantly dampened in huPB10-LS treated animals, as compared to controls. Finally, we found that all five surviving animals, within days after RT exposure, had anti-RT serum IgG titers against epitopes other than huPB10-LS, indicative of active immunization by residual RT and/or RT-immune complexes.
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U2 - 10.1038/s41541-020-0162-0
DO - 10.1038/s41541-020-0162-0
M3 - Article
C2 - 32128254
AN - SCOPUS:85079716400
VL - 5
JO - npj Vaccines
JF - npj Vaccines
SN - 2059-0105
IS - 1
M1 - 13
ER -