Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme
Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme
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DOI：
10.1172/jci.insight.139881
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发表时间：
2020-10-02
期刊：
影响因子：
8
通讯作者：
Asokan, Aravind
中科院分区：
文献类型：
--
作者：
Elmore, Zachary C.;Oh, Daniel K.;Asokan, Aravind
对重组腺相关病毒（AAV）载体的预先存在的体液免疫限制了可治疗的患者群体和人类基因疗法的功效。清除中和抗体（NAb）的方法，如血浆置换和免疫抑制，要么无效，要么引起不良副作用。在这里，我们描述了一种临床相关的策略，使用IgG降解酶（IdeZ）在AAV给药前快速和瞬时降解NAb。我们证明，重组IdeZ有效地切割IgG在狗，猴和人的抗血清。预防性施用的IdeZ在小鼠中切割循环人IgG并防止体内AAV中和。在猕猴中，单次静脉内剂量的IdeZ通过瞬时逆转血清阳性来挽救AAV转导。重要的是，IdeZ在用代表不同群体的个体人供体血清被动免疫的小鼠中有效地切割NAb并拯救AAV转导。我们的抗体清除方法为扩大前瞻性患者队列和提高AAV基因治疗的疗效提供了一种潜在的新范式。
Preexisting humoral immunity to recombinant adeno-associated virus (AAV) vectors restricts the treatable patient population and efficacy of human gene therapies. Approaches to clear neutralizing antibodies (NAbs), such as plasmapheresis and immunosuppression, are either ineffective or cause undesirable side effects. Here, we describe a clinically relevant strategy to rapidly and transiently degrade NAbs before AAV administration using an IgG-degrading enzyme (IdeZ). We demonstrate that recombinant IdeZ efficiently cleaved IgG in dog, monkey, and human antisera. Prophylactically administered IdeZ cleaved circulating human IgG in mice and prevented AAV neutralization in vivo. In macaques, a single intravenous dose of ldeZ rescued AAV transduction by transiently reversing seropositivity. Importantly, IdeZ efficiently cleaved NAbs and rescued AAV transduction in mice passively immunized with individual human donor sera representing a diverse population. Our antibody clearance approach presents a potentially new paradigm for expanding the prospective patient cohort and improving efficacy of AAV gene therapy.