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.

中文翻译：

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cGMP 级 DNA 疫苗 AV-1959D 的表征和临床前评估进入首次人体临床试验。


DNA疫苗AV-1959D针对Aβ肽的N末端表位，已被证明在小鼠、兔子和非人灵长类动物中具有免疫原性，而其治疗功效已在阿尔茨海默病（AD）小鼠模型中得到证实。在此，我们首次报告了 cGMP 级 AV-1959D 疫苗在 Tg2576 AD 小鼠模型中的生物分布和安全性/毒理学研究。我们还在另一个 AD 疾病模型（在临床前转化研究中已确定血管和实质 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。注射两天后的生物分布研究表明，对 Tg2576 小鼠进行单次免疫后，AV-1959D 质粒在注射部位但在远处器官组织中没有高拷贝数。疫苗接种后 60 天，质粒仍存留在一些小鼠的注射部位。在已确定淀粉样蛋白病理学的 Tg2576 小鼠中，我们在使用三剂 AV-1959D 多次免疫后没有观察到短期或长期毒性。对脑淀粉样血管病 (CAA) 倾向 Tg-SwDI 小鼠中重复剂量的 AV-1959D 急性安全性进行评估，未发现磁共振成像 (MRI) 检测到任何免疫治疗诱导的血管性水肿或微出血增加。通过脑组织免疫组织化学测定，用 AV-1959D 多次免疫 Tg-SwDI 小鼠不会诱导 T 细胞和 B 细胞浸润、胶质细胞活化、Aβ 血管沉积或神经元变性（坏死和凋亡），其程度高于对照组。总而言之，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，支持其进入首次人体临床试验。