利用预测性先天性免疫反应评估腺相关病毒载体空壳的免疫原性风险。

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL
Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-09-24 DOI:10.1016/j.xphs.2024.09.006
Nicole Jarvi, Kirk Hofman, Aditi Venkatesh, Emily Gorecki, Sathy V Balu-Iyer
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引用次数: 0

摘要

基因治疗的免疫原性及其对安全性和有效性的影响越来越受到制药业的关注。基因治疗载体(如腺相关病毒(AAV)载体)的独特结构预计会激活先天性免疫系统。先天性免疫激活的风险对安全性和后续适应性免疫反应具有潜在影响,因此了解这种风险至关重要。在这项研究中,我们调查了先天性免疫的主要参与者--树突状细胞、自然杀伤(NK)细胞和补体系统--对 AAV8 包囊的反应。我们还预测了空AAV包被用于AAV基因治疗时的免疫原性风险。与含有基因组的 "全 "AAV8病毒衣壳相比,空AAV8病毒衣壳能更强烈地诱导人和小鼠树突状细胞产生促炎细胞因子和迁移,但 "全 "病毒衣壳会增加共刺激标记物的表达。此外,在 NK 细胞脱颗粒试验中,我们发现空 AAV8 和全 AAV8 包囊的混合物与单独使用其中一种包囊相比,能更强地激活多种 NK 细胞群中 TNF-α、IFN-γ 和 CD107a 的表达。血清补体 C3a 在混合的空 AAV8 和全 AAV8 胶囊制剂中也有更强的诱导作用。先天性免疫激活的风险表明,确定空囊壳的可接受限度非常重要。新型生物模式的免疫原性风险评估将受益于上述体外先天性免疫激活试验,这些试验提供了宝贵的机理信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Immunogenicity risk assessment of empty capsids present in adeno-associated viral vectors using predictive innate immune responses.

Immunogenicity of gene therapy and the impacts on safety and efficacy are of increasing interest in the pharmaceutical industry. Unique structural aspects of gene therapy delivery vectors, such as adeno-associated viral (AAV) vectors, are expected to activate the innate immune system. The risk of innate immune activation is critical to understand due to the potential impacts on safety and on subsequent adaptive immune responses. In this study, we investigated the responses of key innate immune players-dendritic cells, natural killer (NK) cells, and the complement system-to AAV8 capsids. Immunogenicity risk was also predicted in the presence empty AAV capsids for AAV gene therapy. Compared to genome-containing "full" AAV8 capsids, empty AAV8 capsids more strongly induced proinflammatory cytokine production and migration by human and mouse dendritic cells, but the "full" capsid increased expression of co-stimulatory markers. Furthermore, in an NK cell degranulation assay, we found mixtures of empty and full AAV8 capsids to activate expression of TNF-α, IFN-γ, and CD107a more strongly in multiple NK cell populations compared to either capsid type alone. Serum complement C3a was also induced more strongly in the presence of mixed empty and full AAV8 capsid formulations. Risk for innate immune activation suggests the importance to determine acceptable limits of empty capsids. Immunogenicity risk assessment of novel biological modalities will benefit from the aforementioned in vitro innate immune activation assays providing valuable mechanistic information.

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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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