Capsid-specific removal of circulating antibodies to adeno-associated virus vectors
Capsid-specific removal of circulating antibodies to adeno-associated virus vectors
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DOI：
10.1038/s41598-020-57893-z
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发表时间：
2020-01-21
影响因子：
4.6
通讯作者：
Mingozzi, Federico
中科院分区：
文献类型：
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作者：
Bertin, Berangere;Veron, Philippe;Mingozzi, Federico
针对腺相关病毒（AAV）的中和抗体通常在人类中发现。在血清阳性受试者中，载体施用是不可行的，因为抗体即使在低滴度也能中和AAV载体。因此，相当大比例的人被排除在临床试验之外，同样，由于在AAV载体施用后产生高滴度抗体，载体重给药也不可行。血浆置换已被提出作为从血液中去除抗aav抗体的策略。尽管该技术安全且相对有效，但仍存在一些局限性，主要与非特异性去除所有循环IgG有关。在这里，我们开发了一种aav特异性血浆置换柱，该柱被证明可以有效和选择性地消耗抗aav抗体，而不会消耗血浆中的总免疫球蛋白池。我们发现从高滴度纯化的人IgG池和血浆样本中几乎完全去除抗AAV抗体，将滴度降低到允许AAV载体在小鼠中施用的水平。这些结果证明了在体内基因转移的情况下，aav特异性中和抗体耗损方法的概念。
Neutralizing antibodies directed against adeno-associated virus (AAV) are commonly found in humans. In seropositive subjects, vector administration is not feasible as antibodies neutralize AAV vectors even at low titers. Consequently, a relatively large proportion of humans is excluded from enrollment in clinical trials and, similarly, vector redosing is not feasible because of development of high-titer antibodies following AAV vector administration. Plasmapheresis has been proposed as strategy to remove anti-AAV antibodies from the bloodstream. Although safe and relatively effective, the technology has some limitations mainly related to the nonspecific removal of all circulating IgG. Here we developed an AAV-specific plasmapheresis column which was shown to efficiently and selectively deplete anti-AAV antibodies without depleting the total immunoglobulin pool from plasma. We showed the nearly complete removal of anti-AAV antibodies from high titer purified human IgG pools and plasma samples, decreasing titers to levels that allow AAV vector administration in mice. These results provide proof-of-concept of a method for the AAV-specific depletion of neutralizing antibodies in the setting of in vivo gene transfer.