Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro.
Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro.
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DOI：
10.3390/molecules23071700
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发表时间：
2018-07-12
期刊：
影响因子：
--
通讯作者：
Dobrovolskaia MA
中科院分区：
文献类型：
--
作者：
Neun BW;Barenholz Y;Szebeni J;Dobrovolskaia MA
输注反应 (IR) 是接受多种药物产品（包括但不限于纳米技术制剂）治疗的患者中常见的免疫介导副作用。 IR 的机制尚不完全清楚。 IR 对纳米药物研究最透彻的机制之一是补体激活。然而，目前尚不清楚为什么有些患者会对纳米药物产生反应，而另一些患者则不会，以及为什么某些纳米颗粒比其他纳米颗粒更具反应原性。其中一种理论认为，患者体内预先存在的抗聚乙二醇 (PEG) 抗体会启动补体激活和 IR。在这项研究中，我们以聚乙二醇化脂质体阿霉素 (Doxil) 为例研究了这一假设，已知该药物在临床使用时会诱发 IR。被称为敏感个体的补体激活相关假过敏（CARPA）。我们使用来自 C57BL/6 小鼠和 20 名人类捐赠志愿者的血浆进行了体外研究。我们使用小鼠血浆测试了一个经过充分表征的小鼠单克隆抗体库，这些抗体对 PEG 具有不同的特异性和亲和力，因为它与 Doxil 的补体激活有关。我们测定了人血浆中与 PEG、甲氧基-PEG 和聚乙二醇化脂质体结合的预先存在的多克隆抗体的水平，并且我们还评估了 Doxil 的补体激活以及这些人血浆样本中补体抑制因子 H 和 I 的浓度。目前尚不清楚人多克隆抗体的亲和力、特异性和其他特征。我们的数据表明，在体外条件下，一些抗 PEG 抗体有助于 Doxil 的补体激活。然而，这种贡献需要在其他因素的背景下考虑，包括但不限于抗体类别、类型、克隆性、表位特异性、亲和力和滴度。此外，我们的数据有助于了解和提高纳米医学安全性的知识库。
Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti-polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety.
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DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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DOI：
10.3390/molecules23010012
发表时间：
2017-12-21
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Cedrone E;Neun BW;Rodriguez J;Vermilya A;Clogston JD;McNeil SE;Barenholz Y;Szebeni J;Dobrovolskaia MA
通讯作者：
Dobrovolskaia MA
影响因子：
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