Fuchs Sebastian P, Martinez-Navio José M, Rakasz Eva G, Gao Guangping, Desrosiers Ronald C
Department of Pathology & Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA.
Mol Ther Methods Clin Dev. 2019 Nov 26;16:94-102. doi: 10.1016/j.omtm.2019.11.010. eCollection 2020 Mar 13.
A number of publications have described the use of adeno-associated virus (AAV) for the delivery of anti-HIV and anti-simian immunodeficiency virus (SIV) monoclonal antibodies (mAbs) to rhesus monkeys. Anti-drug antibodies (ADAs) have been frequently observed, and long-term AAV-mediated delivery has been inconsistent. Here, we investigated different AAV vector strategies and delivery schemes to rhesus monkeys using the rhesus monkey mAb 4L6. We compared 4L6 immunoglobulin G1 (IgG1) delivery using the AAV1 versus the AAV8 serotype with a cytomegalovirus (CMV) promoter and the use of a muscle-specific versus a liver-specific promoter. Long-term expression levels of 4L6 IgG1 following AAV8-mediated gene transfer were comparable to those following AAV1-mediated gene transfer. AAV1-mediated gene transfer, using a muscle-specific promoter, showed robust ADAs and transiently low 4L6 IgG1 levels that ultimately declined to below detectable levels. Intravenous AAV8-mediated gene transfer, using a liver-specific promoter, also resulted in low levels of delivered 4L6 IgG1, but those low levels were maintained in the absence of any detectable ADAs. Booster injections using AAV1-CMV allowed for increased 4L6 IgG1 serum levels in animals that were primed with AAV8 but not with AAV1. Our results suggest that liver-directed expression may help to limit ADAs and that re-administration of AAV of a different serotype can result in successful long-term delivery of an immunogenic antibody.
许多出版物都描述了使用腺相关病毒（AAV）向恒河猴递送抗HIV和抗猴免疫缺陷病毒（SIV）单克隆抗体（mAb）的情况。经常观察到抗药抗体（ADA），并且AAV介导的长期递送并不稳定。在这里，我们使用恒河猴单克隆抗体4L6研究了向恒河猴递送不同AAV载体策略和方案。我们比较了使用带有巨细胞病毒（CMV）启动子的AAV1血清型与AAV8血清型递送4L6免疫球蛋白G1（IgG1）的情况，以及使用肌肉特异性启动子与肝脏特异性启动子的情况。AAV8介导的基因转移后4L6 IgG1的长期表达水平与AAV1介导的基因转移后相当。使用肌肉特异性启动子的AAV1介导的基因转移显示出强烈的ADA，并且4L6 IgG1水平短暂较低，最终降至可检测水平以下。使用肝脏特异性启动子的静脉内AAV8介导的基因转移也导致递送的4L6 IgG1水平较低，但在没有任何可检测到的ADA的情况下这些低水平得以维持。使用AAV1-CMV进行加强注射可使在用AAV8而非AAV1进行初次免疫的动物中4L6 IgG1血清水平升高。我们的结果表明，肝脏定向表达可能有助于限制ADA，并且重新施用不同血清型的AAV可以成功实现免疫原性抗体的长期递送。
