Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice.
Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice.
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DOI：
10.1182/bloodadvances.2021006359
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发表时间：
2022-04-26
期刊：
影响因子：
7.5
通讯作者：
Doering, Christopher B.
中科院分区：
文献类型：
--
作者：
Lundgren, Taran S.;Denning, Gabriela;Stowell, Sean R.;Spencer, H. Trent;Doering, Christopher B.
在血友病A小鼠中，AAV-FVIII基因治疗后，初始FVIII暴露率是免疫原性的最强预测因子。较慢的初始FVIII暴露率演变为正常或更高范围内的稳态FVIII水平，支持免疫耐受。血友病A的新治疗方案的发展进展是普遍的。然而，抗因子VIII （FVIII）中和抗体（抑制剂）对现有FVIII产品的反应仍然是一个主要的治疗挑战。尽管一些新产品被设计为在抑制剂存在的情况下发挥作用，但它们并没有具体解决抑制剂发展的免疫原性风险或机制原因，这些尚不清楚。此外，大多数支持临床基因治疗项目的临床前研究报告了动物模型中的免疫原性信号，特别是在较高载体剂量和有时使用多种载体设计时。在这些情况下，免疫原性风险因素的确定，竞争载体设计的比较免疫原性，以及获得有意义的预后数据的潜力仍然相对未被探索。此外，仍有机会研究临床基因治疗作为标准免疫耐受诱导治疗的替代方案。目前的研究旨在通过在a型血友病小鼠模型中对4种腺相关病毒（AAV）候选载体编码2种不同的FVIII转基因的纵向剂量反应评估来解决这些问题。血浆FVIII活性和抗FVIII抗体数据用于生成药代动力学模型，该模型：(1)确定初始AAV-FVIII产物表达动力学是抑制剂发展的主要危险因素；(2)预测了实现免疫耐受的治疗窗口；(3)证明了基于基因治疗的免疫耐受诱导的证据。尽管临床前免疫原性检测的预测价值存在已知的局限性，但这些研究可以揭示或支持设计原则的发展，这些原则可以指导安全有效的遗传药物的开发。
Initial FVIII exposure rate is the strongest predictor of immunogenicity after AAV-FVIII gene therapy in hemophilia A mice. Slower initial FVIII exposure rates evolving to steady-state FVIII levels in the normal or higher range support immune tolerance. Advances in the development of novel treatment options for hemophilia A are prevalent. However, the anti–factor VIII (FVIII) neutralizing antibody (inhibitor) response to existing FVIII products remains a major treatment challenge. Although some novel products are designed to function in the presence of inhibitors, they do not specific address the immunogenicity risk or mechanistic causes of inhibitor development, which remain unclear. Furthermore, most preclinical studies supporting clinical gene therapy programs have reported immunogenicity signals in animal models, especially at higher vector doses and sometimes using multiple vector designs. In these settings, immunogenicity risk factor determination, comparative immunogenicity of competing vector designs, and the potential for obtaining meaningful prognostic data remain relatively unexplored. Additionally, there remains the opportunity to investigate clinical gene therapy as an alternative to standard immune tolerance induction therapy. The current study was designed to address these issues through longitudinal dose-response evaluation of 4 adeno-associated viral (AAV) vector candidates encoding 2 different FVIII transgenes in a murine model of hemophilia A. Plasma FVIII activity and anti-FVIII antibody data were used to generate a pharmacokinetic model that (1) identifies initial AAV-FVIII product expression kinetics as the dominant risk factor for inhibitor development, (2) predicts a therapeutic window where immune tolerance is achieved, and (3) demonstrates evidence of gene therapy–based immune tolerance induction. Although there are known limitations to the predictive value of preclinical immunogenicity testing, these studies can uncover or support the development of design principles that can guide the development of safe and effective genetic medicines.
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