Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USA.
Neurobiol Dis. 2020 Jun;139:104823. doi: 10.1016/j.nbd.2020.104823. Epub 2020 Feb 28.
The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aβ peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aβ pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aβ, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.
一种针对 Aβ 肽 N 端表位的 DNA 疫苗 AV-1959D 已在小鼠、兔和非人灵长类动物中证明具有免疫原性，而其在阿尔茨海默病（AD）小鼠模型中的治疗效果也已得到证实。在这里，我们首次报告了 IND 相容的 AV-1959D 疫苗的 cGMP 级别的生物分布和安全性/毒理学研究结果，该疫苗在 AD 的 Tg2576 小鼠模型中进行了研究。我们还在另一种 AD 疾病模型，即具有血管和实质 Aβ 病理学的 Tg-SwDI 小鼠中，测试了 AV-1959D 的急性神经病理学安全性概况，这是在临床前转化研究中进行的。在 Tg2576 小鼠中进行的单次免疫后两天的生物分布研究显示，在注射部位的 AV-1959D 质粒的拷贝数很高，但在远处器官的组织中则没有。在接种疫苗 60 天后，一些小鼠的注射部位仍存在质粒。在具有淀粉样蛋白病理学的 Tg2576 小鼠中，我们在多次免疫三剂 AV-1959D 后未观察到短期或长期毒性。在易发生脑淀粉样血管病（CAA）的 Tg-SwDI 小鼠中评估 AV-1959D 的重复剂量急性安全性时，未通过磁共振成像（MRI）检测到任何免疫治疗引起的血管源性水肿或增加的微出血。在 Tg-SwDI 小鼠中进行多次免疫接种 AV-1959D 不会引起 T 和 B 细胞浸润、神经胶质激活、血管中 Aβ 的沉积或神经元变性（坏死和凋亡），其程度比对照组通过脑组织免疫组化检测到的程度更大。综上所述，来自两种不同 AD 小鼠模型的安全性数据证实了 cGMP 级 AV-1959D 疫苗具有良好的安全性，支持其推进至首次人体临床试验。
