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NPJ Vaccines. 2020 Feb 13;5:13. doi: 10.1038/s41541-020-0162-0. eCollection 2020.

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

Author information

1
1Tulane National Primate Research Center, Covington, LA 70433 USA.
2
2Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208 USA.
3
3Mapp Biopharmaceutical, Inc, San Diego, CA 92121 USA.
4
Clinical Pharmacology Branch, Walter Reed Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910 USA.
5
6Present Address: Vaccines and Therapeutics Division, Defense Threat Reduction Agency, 8725 John J. Kingman Rd., Fort Belvoir, VA 22060 USA.
6
5Departments of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA.

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.

KEYWORDS:

Antibodies; Bacterial toxins; Vaccines

Conflict of interest statement

Competing interestsZ.B., L.C., M.C., D.K. and N.M. are Mapp Biopharmaceutical employees and shareholders. K.W. and L.Z. are employees, shareholders, and co-owners of Mapp Biopharmaceutical. The other authors declare no competing interests.

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