Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

Chad J. Roy, Greta Van Slyke, Dylan Ehrbar, Zachary A. Bornholdt, Miles B. Brennan, Lioudmila Campbell, Michelle Chen, Do Kim, Neil Mlakar, Kevin J. Whaley, Jeffrey W. Froude, Fernando J. Torres-Velez, Ellen Vitetta, Peter J. Didier, Lara Doyle-Meyers, Larry Zeitlin, Nicholas J. Mantis

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number13
Journalnpj Vaccines
Volume5
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Infectious Diseases
  • Pharmacology (medical)

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    Roy, C. J., Van Slyke, G., Ehrbar, D., Bornholdt, Z. A., Brennan, M. B., Campbell, L., Chen, M., Kim, D., Mlakar, N., Whaley, K. J., Froude, J. W., Torres-Velez, F. J., Vitetta, E., Didier, P. J., Doyle-Meyers, L., Zeitlin, L., & Mantis, N. J. (2020). Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin. npj Vaccines, 5(1), [13]. https://doi.org/10.1038/s41541-020-0162-0