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JCI Insight. 2019 Jan 10;4(1). pii: 124771. doi: 10.1172/jci.insight.124771. [Epub ahead of print]

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin.

Author information

1
Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
2
Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
3
Mapp Biopharmaceutical Inc., San Diego, California, USA.
4
Departments of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Abstract

Ricin toxin (RT) ranks at the top of the list of bioweapons of concern to civilian and military personnel alike, due to its high potential for morbidity and mortality after inhalation. In nonhuman primates, aerosolized ricin triggers severe acute respiratory distress characterized by perivascular and alveolar edema, neutrophilic infiltration, and severe necrotizing bronchiolitis and alveolitis. There are currently no approved countermeasures for ricin intoxication. Here, we report the therapeutic potential of a humanized mAb against an immunodominant epitope on ricin's enzymatic A chain (RTA). Rhesus macaques that received i.v. huPB10 4 hours after a lethal dose of ricin aerosol exposure survived toxin challenge, whereas control animals succumbed to ricin intoxication within 30 hours. Antibody intervention at 12 hours resulted in the survival of 1 of 5 monkeys. Changes in proinflammatory cytokine, chemokine, and growth factor profiles in bronchial alveolar lavage fluids before and after toxin challenge successfully clustered animals by treatment group and survival, indicating a relationship between local tissue damage and experimental outcome. This study represents the first demonstration, to our knowledge, in nonhuman primates that the lethal effects of inhalational ricin exposure can be negated by a drug candidate, and it opens up a path forward for product development.

KEYWORDS:

Immunology; Pulmonology; Toxins/drugs/xenobiotics

PMID:
30626745
DOI:
10.1172/jci.insight.124771
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