PDF(Pubmed)
Abstract：
Gene transfer therapies utilizing adeno-associated virus (AAV) vectors involve a complex drug design with multiple components that may impact immunogenicity. Valoctocogene roxaparvovec is an AAV serotype 5 (AAV5)-vectored gene therapy for the treatment of hemophilia A that encodes a B-domain-deleted human factor VIII (FVIII) protein controlled by a hepatocyte-selective promoter. Following previous results from the first-in-human phase 1/2 clinical trial, we assessed AAV5-capsid- and transgene-derived FVIII-specific immune responses with 2 years of follow-up data from GENEr8-1, a phase 3, single-arm, open-label study in 134 adult men with severe hemophilia A. No FVIII inhibitors were detected following administration of valoctocogene roxaparvovec. Immune responses were predominantly directed toward the AAV5 capsid, with all participants developing durable anti-AAV5 antibodies. Cellular immune responses specific for the AAV5 capsid were detected in most participants by interferon-γ enzyme-linked immunosorbent spot assay 2 weeks following dose administration and declined or reverted to negative over the first 52 weeks. These responses were weakly correlated with alanine aminotransferase elevations and showed no association with changes in FVIII activity. FVIII-specific cellular immune responses were less frequent and more sporadic compared with those specific for AAV5 and showed no association with safety or efficacy parameters.
摘要：
利用腺相关病毒(AAV)载体的基因转移治疗涉及具有可能影响免疫原性的多种组分的复杂药物设计。Valoctocogeneroxaparvovec是一种AAV血清型5（AAV5）载体基因疗法，用于治疗血友病A，其编码由肝细胞选择性启动子控制的B结构域缺失的人VIII因子（FVIII）蛋白。根据人类首次1/2期临床试验的先前结果，我们评估了AAV5衣壳和转基因衍生的FVIII特异性免疫应答2年的随访数据从GENEr8-1，3期，单臂，在134名患有重度血友病A的成年男性中进行的开放标签研究,在给予丙可可基因roxaparvovec后未检测到FVIII抑制剂.免疫反应主要针对AAV5衣壳，所有参与者都开发出持久的抗AAV5抗体。在剂量给药后2周，通过干扰素-酶联免疫吸附斑点测定法在大多数参与者中检测到AAV5衣壳的特异性细胞免疫反应，并在前52周内下降或恢复为阴性。这些反应与丙氨酸转氨酶升高弱相关，与FVIII活性变化无关。与AAV5的特异性细胞免疫反应相比，FVIII特异性细胞免疫反应频率更低，更零星，并且与安全性或功效参数无关。
