Pseudo-anaphylaxis to Polyethylene Glycol (PEG)-Coated Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine Model of Human Infusion Reactions
Pseudo-anaphylaxis to Polyethylene Glycol (PEG)-Coated Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine Model of Human Infusion Reactions
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DOI：
10.1021/acsnano.9b03942
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发表时间：
2019-08-01
期刊：
影响因子：
17.1
通讯作者：
Szebeni, Janos
中科院分区：
文献类型：
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作者：
Kozma, Gergely Tibor;Meszaros, Tamas;Szebeni, Janos
聚乙二醇（PEG）涂层纳米药物可能会导致轻度至重度超敏反应（HSR），偶尔可能危及生命甚至致命。这种现象代表了使用这些药物的未解决的免疫屏障，但其机制知之甚少。该研究表明，在猪中单次静脉注射低剂量的PEG化脂质体（Doxebo）诱导血液中抗PEG IgM的大量升高，在第7-9天达到峰值，并在6周内下降。在血清转化期间，PEG-脂质体的推注导致2-3分钟内的类速发过敏反应性休克（假性速发过敏反应），尽管对未处理动物的类似治疗仅导致轻度血流动力学紊乱。平行测量肺动脉压（PAP）和sCSb-9在血液中，分别作为HSR和补体激活的措施，显示了一致的上升，在3分钟内和15分钟内下降的两个变量，这表明补体激活和肺动脉高压之间的因果关系。我们还观察到血液中抗PEG IgM在几分钟内快速下降，与对照相比，免疫动物脾脏中PEG化脂质体与IgM+ B细胞的结合增加，免疫猪血清中PEG化脂质体的C3转化增加。这些观察结果共同表明抗PEG IgM与PEG化脂质体快速结合，导致补体通过经典途径活化，导致过敏样休克和脂质体IgM复合物的加速血液清除。这些数据表明，补体激活在聚乙二醇化纳米药物的严重HSR中发挥着因果作用，并且猪可用作危险识别模型，以评估临床前安全性研究中HSR的风险。
Polyethylene glycol (PEG)-coated nanopharmaceuticals can cause mild to severe hypersensitivity reactions (HSRs), which can occasionally be life threatening or even lethal. The phenomenon represents an unsolved immune barrier to the use of these drugs, yet its mechanism is poorly understood. This study showed that a single i.v. injection in pigs of a low dose of PEGylated liposomes (Doxebo) induced a massive rise of anti-PEG IgM in blood, peaking at days 7-9 and declining over 6 weeks. Bolus injections of PEG-liposomes during seroconversion resulted in anaphylactoid shock (pseudo-anaphylaxis) within 2-3 min, although similar treatments of na ve animals led to only mild hemodynamic disturbance. Parallel measurement of pulmonary arterial pressure (PAP) and sCSb-9 in blood, taken as measures of HSR and complement activation, respectively, showed a concordant rise of the two variables within 3 min and a decline within 15 min, suggesting a causal relationship between complement activation and pulmonary hypertension. We also observed a rapid decline of anti-PEG IgM in the blood within minutes, increased binding of PEGylated liposomes to IgM+ B cells in the spleen of immunized animals compared to control, and increased C3 conversion by PEGylated liposomes in the serum of immunized pigs. These observations taken together suggest rapid binding of anti-PEG IgM to PEGylated liposomes, leading to complement activation via the classical pathway, entailing anaphylactoid shock and accelerated blood clearance of liposome IgM complexes. These data suggest that complement activation plays a causal role in severe HSRs to PEGylated nanomedicines and that pigs can be used as a hazard identification model to assess the risk of HSRs in preclinical safety studies.