TY - JOUR
T1 - Rescue of rhesus macaques from the lethality of aerosolized ricin toxin
AU - Roy, Chad J.
AU - Ehrbar, Dylan J.
AU - Bohorova, Natasha
AU - Bohorov, Ognian
AU - Kim, Do
AU - Pauly, Michael
AU - Whaley, Kevin
AU - Rong, Yinghui
AU - Torres-Velez, Fernando J.
AU - Vitetta, Ellen S.
AU - Didier, Peter J.
AU - Doyle-Meyers, Lara
AU - Zeitlin, Larry
AU - Mantis, Nicholas J.
N1 - Publisher Copyright:
© Copyright 2019, American Society for Clinical Investigation.
PY - 2019/1/10
Y1 - 2019/1/10
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.124771
DO - 10.1172/jci.insight.124771
M3 - Article
C2 - 30626745
AN - SCOPUS:85069705311
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 1
M1 - e124771
ER -