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.
Highlights
The Centers for Disease Control and Prevention (CDC), along with other U.S government and international agencies, recognize that the deliberate release of biological toxins and highly infectious agents into the public sphere remains a threat to both military and civilian personnel.[1,2] Ricin toxin (RT), for example, was recently ranked by NATO’s Biomedical Advisory Council as a high potential threat because of its accessibility, stability, and extreme toxicity, especially by inhalation.[3]
As a case in point, we recently reported that huPB10, a humanized monoclonal antibody (MAb) directed against an immunodominant epitope near RTA’s active site, was able to rescue Rhesus macaques from a 3 × LD50 RT aerosol challenge when administered ~4–6 h after toxin exposure.[11]
Recombinant huPB10 IgG variants with extended serum half-lives following RT challenge revealed coalescing hemorrhage with frothy exudate marked by fibrin in lung parenchyma, as we have reported previously.[11]
Summary
The Centers for Disease Control and Prevention (CDC), along with other U.S government and international agencies, recognize that the deliberate release of biological toxins and highly infectious agents into the public sphere remains a threat to both military and civilian personnel.[1,2] Ricin toxin (RT), for example, was recently ranked by NATO’s Biomedical Advisory Council as a high potential threat because of its accessibility, stability, and extreme toxicity, especially by inhalation.[3]. Within the lumen of the ER, RTA is liberated from RTB and translocated into the cytoplasm where it irreversibly inactivates ribosomes by depurination of a conserved adenosine moiety within the sarcin/ricin loop of 28 S rRNA.[5,6] Ribosome arrest triggers the so-called ribotoxic-stress response (RSR), which, in turn, activates stress activated protein kinase pathways and programmed cell death (PCD)
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