Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin.
Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin.
复制标题
使用延长半衰期的单克隆抗体进行被动免疫可以保护恒河猴免受雾化蓖麻毒素的侵害。
DOI：
10.1038/s41541-020-0162-0
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发表时间：
2020
期刊：
影响因子：
9.2
通讯作者：
Doyle-Meyers,
中科院分区：
文献类型：
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作者：
Roy,ChadJ;VanSlyke,Greta;Ehrbar,Dylan;Bornholdt,ZacharyA;Brennan,MilesB;Campbell,Lioudmila;Chen,Michelle;Kim,Do;Mlakar,Neil;Whaley,KevinJ;Froude,JeffreyW;Torres-Velez,FernandoJ;Vitetta,Ellen;Didier,PeterJ;Doyle-Meyers,
蓖麻毒素（RT）是一种B类生物威胁剂，吸入后可引起急性呼吸窘迫综合征，其特征为促炎细胞因子和趋化因子的产生、嗜酸性渗出物和肺水肿。RT暴露的严重性归因于毒素的B亚单位（RT B）对肺泡巨噬细胞和气道上皮细胞的嗜性，以及毒素的酶亚单位（RTA）非常有效的核糖体失活特性。虽然目前还没有疫苗或治疗方法被批准用于预防RT中毒，但我们最近描述了一种人源化抗RTA IgG 1 MAb huPB 10，如果在毒素暴露后数小时内通过静脉（IV）输注给药，则能够将非人灵长类动物（NHP）从致死剂量RT气雾剂攻击中拯救出来。我们现在已经设计了该MAb的延长血清半衰期变体huPB 10-LS，并将其作为暴露前预防剂进行了评估。接受单次静脉输注（25 mg/kg）huPB 10-LS的5只恒河猴在致死剂量气雾剂RT攻击后28天存活，而3只对照动物在48小时内死于RT中毒。huPB 10-LS处理的动物在毒素损伤后的数小时和数天内保持临床正常，表明预先存在的抗体水平足以局部中和RT。此外，与对照相比，在RT攻击后24小时收集的血清和BAL液中的促炎标志物在huPB 10-LS处理的动物中显著减弱。最后，我们发现所有5只存活动物在RT暴露后数天内均具有针对huPB 10-LS以外的表位的抗RT血清IgG滴度，表明通过残留RT和/或RT-免疫复合物的主动免疫。
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 IgG1MAb, 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.