Majowicz Anna, Nijmeijer Bart, Lampen Margit H, Spronck Lisa, de Haan Martin, Petry Harald, van Deventer Sander J, Meyer Christian, Tangelder Marco, Ferreira Valerie
uniQure N.V., Amsterdam, the Netherlands.
Mol Ther Methods Clin Dev. 2019 May 28;14:27-36. doi: 10.1016/j.omtm.2019.05.009. eCollection 2019 Sep 13.
Currently, individuals with pre-existing neutralizing antibodies (NABs) against adeno-associated virus (AAV) above titer of 5 are excluded from systemic AAV-based clinical trials. In this study we explored the impact of pre-existing anti-AAV5 NABs on the efficacy of AAV5-based gene therapy. AMT-060 (AAV5-human FIX) was evaluated in 10 adults with hemophilia B who tested negative for pre-existing anti-AAV5 NABs using a GFP-based assay. In this study, using a more sensitive luciferase-based assay, we show that 3 of those 10 patients tested positive for anti-AAV5 NABs. However, no relationship was observed between the presence of pre-treatment anti-AAV5 NABs and the therapeutic efficacy of AMT-060. Further studies in non-human primates (NHPs) showed that AAV5 transduction efficacy was similar following AMT-060 treatment, irrespective of the pre-existing anti-AAV5 NABs titers. We show that therapeutic efficacy of AAV5-mediated gene therapy was achieved in humans with pre-existing anti-AAV5 NABs titers up to 340. Whereas in NHPs circulating human factor IX (hFIX) protein was achieved, at a level therapeutic in humans, with pre-existing anti-AAV5 NABs up to 1030. Based on those results, no patients were excluded from the AMT-061 (AAV5-hFIX-Padua) phase IIb clinical trial (n = 3). All three subjects presented pre-existing anti-AAV5 NABs, yet had therapeutic hFIX activity after AMT-061 administration.
目前，预先存在的针对腺相关病毒（AAV）且滴度高于5的中和抗体（NABs）的个体被排除在基于全身性AAV的临床试验之外。在本研究中，我们探讨了预先存在的抗AAV5 NABs对基于AAV5的基因治疗疗效的影响。使用基于绿色荧光蛋白（GFP）的检测方法，对10名预先存在的抗AAV5 NABs检测呈阴性的B型血友病成年患者进行了AMT-060（AAV5-人FIX）评估。在本研究中，使用更灵敏的基于荧光素酶的检测方法，我们发现这10名患者中有3名抗AAV5 NABs检测呈阳性。然而，未观察到治疗前抗AAV5 NABs的存在与AMT-060的治疗疗效之间存在关联。在非人类灵长类动物（NHP）中的进一步研究表明，无论预先存在的抗AAV5 NABs滴度如何，AMT-060治疗后AAV5转导效率相似。我们表明，预先存在的抗AAV5 NABs滴度高达340的人类实现了AAV5介导的基因治疗的疗效。而在NHP中，预先存在的抗AAV5 NABs高达1030时，循环中的人凝血因子IX（hFIX）蛋白达到了对人类有治疗作用的水平。基于这些结果，没有患者被排除在AMT-061（AAV5-hFIX-Padua）IIb期临床试验（n = 3）之外。所有三名受试者都预先存在抗AAV5 NABs，但在给予AMT-061后具有治疗性hFIX活性。
