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

• Published in: npj vaccines Vol. 5; no. 1; p. 13
• Main Authors: Roy, Chad J., Van Slyke, Greta, Ehrbar, Dylan, Bornholdt, Zachary A., Brennan, Miles B., Campbell, Lioudmila, Chen, Michelle, Kim, Do, Mlakar, Neil, Whaley, Kevin J., Froude, Jeffrey W., Torres-Velez, Fernando J, Vitetta, Ellen, Didier, Peter J., Doyle-Meyers, Lara, Zeitlin, Larry, Mantis, Nicholas J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.02.2020; Nature Publishing Group
• Subjects: 631/250/2152/2153/1291; 631/250/590; 631/326/41/1319; Aerosols; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Edema; Immune system; Immunization; Immunoglobulins; Infectious Diseases; Inhalation; Medical Microbiology; Monkeys & apes; Monoclonal antibodies; Poisons; Primates; Public Health; Toxicity; Toxins; Vaccine; Vaccines; Virology; Bacterial toxins; Antibodies; Vaccines
• ISSN: 2059-0105; 2059-0105
• DOI: 10.1038/s41541-020-0162-0

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 IgG 1 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.