Accelerated Blood Clearance of Lipid Nanoparticles Entails a Biphasic Humoral Response of B-1 Followed by B-2 Lymphocytes to Distinct Antigenic Moieties.
Accelerated Blood Clearance of Lipid Nanoparticles Entails a Biphasic Humoral Response of B-1 Followed by B-2 Lymphocytes to Distinct Antigenic Moieties.
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DOI：
10.4049/immunohorizons.1900029
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发表时间：
2019-07-11
期刊：
影响因子：
--
通讯作者：
Hoge, Stephen
中科院分区：
文献类型：
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作者：
Besin, Gilles;Milton, Jaclyn;Hoge, Stephen
加速血液清除（ABC）是指某些药物在第二次或以后给药时迅速从血液中清除的现象。ABC已在许多脂质输送载体中被观察到，包括脂质体和脂质纳米颗粒（LNP）。先前的研究已经证明了针对聚乙二醇基序的体液反应在清除中的作用，但我们对ABC的机制的理解仍然存在重大差距，并且在临床环境中限制ABC影响的策略一直难以实现。mRNA治疗有很大的前景，但需要在包封输送系统中长期给药，其中LNP是临床最先进的。在本研究中，我们在体内和体外研究了ABC对mrna配制的LNP的作用机制。我们提供的证据表明，基于LNP直接激活B-1淋巴细胞的先前未被认识到的能力，mrna配制的LNP的ABC是戏剧性的，并且进展迅速，导致在初始注射后产生抗磷胆碱IgM抗体。反复注射后，B-2淋巴细胞也被激活并产生典型的抗聚乙二醇适应性体液反应。因此，ABC对磷酸化胆碱/ lnp包封mRNA的反应是早期B-1淋巴细胞和后期B-2淋巴细胞反应的结合。
Accelerated blood clearance (ABC) is a phenomenon in which certain pharmaceutical agents are rapidly cleared from the blood upon second and subsequent administrations. ABC has been observed for many lipid-delivery vehicles, including liposomes and lipid nanoparticles (LNP). Previous studies have demonstrated a role for humoral responses against the polyethylene glycol motifs in clearance, but significant gaps remain in our understanding of the mechanism of ABC, and strategies for limiting the impact of ABC in a clinical setting have been elusive. mRNA therapeutics have great promise, but require chronic administration in encapsulating delivery systems, of which LNP are the most clinically advanced. In this study, we investigate the mechanisms of ABC for mRNA-formulated LNP in vivo and in vitro. We present evidence that ABC of mRNA-formulated LNP is dramatic and proceeds rapidly, based on a previously unrecognized ability of LNP to directly activate B-1 lymphocytes, resulting in the production of antiphosphorylcholine IgM Abs in response to initial injection. Upon repeated injections, B-2 lymphocytes also become activated and generate a classic anti-polyethylene glycol adaptive humoral response. The ABC response to phosphorylcholine/LNP-encapsulated mRNA is therefore a combination of early B-1 lymphocyte and later B-2 lymphocyte responses.