Treatment of Alzheimer's disease by clearing both tau and amyloid beta pathologies

通过清除 tau 蛋白和 β 淀粉样蛋白病理来治疗阿尔茨海默病

基本信息

批准号：
10545157
负责人：
KHALID IQBAL
金额：
$ 50万
依托单位：
PHANES BIOTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545157
关键词：
3xTg-AD mouse AD transgenic mice Abeta clearance Active Immunization Adverse effects Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient American Amyloid beta-Protein Antibodies Antibody Affinity Antibody Therapy Autopsy Axon Belief Binding Biochemical Biological Biotechnology Brain Cause of Death Cell Line Clinical Treatment Clinical Trials Cognition Combined Modality Therapy Contracts Cross Reactions Dementia Disease Dose Family Freezing Funding Generations Goals Healthcare Heterogeneity Human Immunization Immunize Immunotherapy Impaired cognition Injections Intravenous Laboratories Lead Legal patent Lesion Licensing Monoclonal Antibodies Mus Natural regeneration Nature Neocortex Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurosciences Onset of illness Outcome Pathology Patients Peptides Persons Pharmaceutical Preparations Phase Privatization Process Progressive Supranuclear Palsy Proteins Rattus Research Project Grants Senile Plaques Side Site Small Business Innovation Research Grant Specificity Switzerland Tail Tauopathies Testing Tissues United States Veins abnormally phosphorylated tau antibody immunotherapy base beta amyloid pathology commercialization cost density disorder prevention drug development effective therapy healthy volunteer human old age (65+)humanized antibody hyperphosphorylated tau mouse model phase 1 study preclinical study prevent protein TDP-43 safety study success tau Proteins transgenic model of alzheimer disease

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is the sixth leading cause of death in the United States. Nearly six million Americans suffer from AD, at an annual cost of almost $300 billion for their health care. At present, no effective treatment of this disease is available. If no treatment is found that can inhibit, prevent, or cure this disease, the number of cases will triple by 2050. Thus, there is an urgent need to develop an effective treatment for AD. AD is histopathologically characterized by the occurrence of numerous Aβ plaques and neurofibrillary tangles of abnormally hyperphosphorylated tau in the brain. Tau pathology of hyperphosphorylated tau is also a hallmark lesion of several related neurodegenerative diseases, called tauopathies. The density of tau pathology, and not of Aβ plaques, correlates with the degree of dementia in AD patients. There is increasing belief in the field that the clearance of both Aβ or tau pathologies could be required to successfully treat AD. So far, none of the antibodies used in human clinical trials have had such activity. We have generated several high-affinity tau mouse monoclonal antibodies, and one of these, tau antibody 43D to human tau 6-18, can clear not only tau pathology but also Aβ pathology and rescued cognitive impairment in the 3xTg-AD transgenic mouse model of AD and tauopathy. We propose to further develop this unique tau antibody for immunotherapy of AD and related conditions. The PI has patented 43D for the treatment of AD and related neurodegenerative disorders. The specific aims of this SBIR Phase I application are (1) to study the humanization of the tau mouse monoclonal antibodies 43D and 77E9 and (2) to study the immunotherapy activities of the humanized antibodies from Aim 1 in comparison with the corresponding mouse monoclonals in 3xTg-AD transgenic mice treated with AD ptau. Hyperphosphorylated tau (ptau), free from any Aβ and TDP43, will be isolated from AD frozen autopsied AD brain and used to induce tau seeding and spread in 3xTg-AD mice, which will be immunized with humanized 43D in comparison with a Aβ-negative effective tau antibody 77E9 to tau 184-195 and the corresponding mouse monoclonals. The effect of immunization of tau and Aβ pathologies will be evaluated immunohistochemically and biochemically. These Phase I studies will be followed by a Phase II application on generation of a cell line of the lead humanized antibody with similar or higher activity as the corresponding mouse monoclonal and then leading to large-scale GMP manufacture, IND, and test of cross-reactions and non-target tissue binding, along with the safety studies and human clinical trials. The successful completion of the proposed studies will lead to Phase I human clinical trials in healthy volunteers and Phase II and then Phase III human clinical trials on AD and related neurodegenerative conditions and will potentially lead to the treatment and prevention of these diseases. At Phanes Biotech, we believe that given its multifactorial nature and heterogeneity, AD could require a combination therapy. While on one side we are developing the neurotrophic compound P021 to stimulate regeneration of the brain, combining it with tau immunotherapy, which can inhibit neurodegeneration, could further increase our success and is the long-term goal of our company.

项目概要阿尔茨海默病 (AD) 是美国近 600 万美国人的第六大死因。患有 AD 的患者每年花费近 3000 亿美元用于治疗，目前尚无有效的治疗方法。如果没有发现可以抑制、预防或治愈这种疾病的治疗方法，则该疾病的数量。到 2050 年，AD 病例将增加两倍。因此，迫切需要开发一种有效的 AD 治疗方法。组织病理学特征为大量 Aβ 斑块和神经原纤维缠结的出现大脑中异常过度磷酸化的 tau 蛋白也是一个标志。几种相关神经退行性疾病的病变，称为 tau 蛋白病变，而不是 tau 蛋白病理学的密度。 Aβ 斑块的数量与 AD 患者的痴呆程度相关，这一领域越来越多的人相信这一点。成功治疗 AD 可能需要清除 Aβ 或 tau 蛋白病理。在人体临床试验中使用的抗体已经具有这样的活性，我们已经产生了几种高亲和力的tau蛋白。小鼠单克隆抗体，其中之一，针对人 tau 6-18 的 tau 抗体 43D，不仅可以清除 tau 病理学以及 Aβ 病理学并挽救了 3xTg-AD 转基因小鼠模型中的认知障碍我们建议进一步开发这种独特的 tau 抗体，用于 AD 及相关疾病的免疫治疗。 PI 已获得用于治疗 AD 和相关神经退行性疾病的 43D 专利。该 SBIR 第一阶段申请的具体目标是 (1) 研究 tau 小鼠单克隆抗体的人源化抗体 43D 和 77E9 以及 (2) 研究目标 1 中的人源化抗体的免疫治疗活性与用 AD ptau 处理的 3xTg-AD 转基因小鼠中相应的小鼠单克隆抗体进行比较。高度磷酸化的 tau (ptau)，不含任何 Aβ 和 TDP43，将从 AD 冷冻尸检 AD 中分离出来大脑并用于诱导 tau 播种并在 3xTg-AD 小鼠中传播，该小鼠将接受人源化免疫图43D与针对tau 184-195的Aβ阴性有效tau抗体77E9以及相应小鼠的比较将通过免疫组织化学方法评估 tau 和 Aβ 病理的免疫效果。这些第一阶段研究之后将进行第二阶段应用，以产生细胞系。先导人源化抗体与相应的小鼠单克隆抗体具有相似或更高的活性，然后先导大规模 GMP 生产、IND 以及交叉反应和非靶组织结合测试，以及安全性研究和人体临床试验的成功完成将导致第一阶段的研究。在健康志愿者中进行的人体临床试验以及针对 AD 和相关疾病的 II 期和 III 期人体临床试验神经退行性疾病，并有可能导致这些疾病的治疗和预防。 Phanes Biotech，我们认为，鉴于 AD 的多因素性质和异质性，AD 可能需要结合使用一方面，我们正在开发神经营养化合物 P021 来刺激神经细胞的再生。大脑，将其与可抑制神经退行性变的 tau 免疫疗法相结合，可以进一步提高我们的成功，是我们公司的长期目标。