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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：
10772916
负责人：
KHALID IQBAL
金额：
$ 5.37万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10772916
关键词：
3xTg-AD mouse AD transgenic mice Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia American Amyloid beta-Protein Antibodies Autopsy Belief Binding Biochemical Biological Biotechnology Brain Cause of Death Cell Line Clinical Treatment Clinical Trials Combined Modality Therapy Cross Reactions Dementia Disease Freezing Generations Goals Healthcare Heterogeneity Human Immunization Immunize Immunotherapy Impaired cognition Lead Legal patent Lesion Monoclonal Antibodies Mus Natural regeneration Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Pathology Persons Pharmaceutical Preparations Phase Research Project Grants Senile Plaques Side Small Business Innovation Research Grant Tauopathies Testing Tissues United States abnormally phosphorylated tau antibody immunotherapy beta amyloid pathology cost density disorder prevention effective therapy healthy volunteer humanized antibody hyperphosphorylated tau manufacture mouse model phase 1 study prevent protein TDP-43 safety study success tau Proteins

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.

项目摘要阿尔茨海默病（AD）是美国第六大死亡原因。近六百万美国人他们每年的医疗保健费用近3000亿美元。目前尚无有效治疗方法这种疾病是可用的。如果没有发现可以抑制、预防或治愈这种疾病的治疗方法，到2050年病例将增加两倍因此，迫切需要开发有效的AD治疗方法。AD是组织病理学特征为发生大量Aβ斑块和神经纤维缠结，异常过度磷酸化的tau蛋白过度磷酸化tau蛋白的病理学也是一个标志几种相关的神经退行性疾病的病变，称为tau蛋白病。tau蛋白病理学的密度，而不是 Aβ斑块的形成与AD患者的痴呆程度相关。该领域越来越多的人相信，可能需要清除Aβ或tau病理以成功治疗AD。到目前为止，用于人类临床试验的抗体具有这种活性。我们已经产生了几个高亲和力的tau蛋白小鼠单克隆抗体，其中之一，针对人tau 6-18的tau抗体43 D，不仅可以清除tau 在3xTg-AD转基因小鼠模型中， AD和tau蛋白病。我们建议进一步开发这种独特的tau抗体，用于AD和相关疾病的免疫治疗。条件PI已获得43 D治疗AD和相关神经退行性疾病的专利。的该SBIR I期应用的具体目的是（1）研究tau小鼠单克隆抗体的人源化，抗体43 D和77 E9，以及（2）研究来自Aim 1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相比。将从AD冷冻尸检的AD中分离不含任何Aβ和TDP 43的过度磷酸化tau（ptau）脑，并用于诱导tau接种和在3xTg-AD小鼠中扩散，所述小鼠将用人源化的 43 D与针对tau 184-195的Aβ-阴性有效tau抗体77 E9和相应小鼠的比较单克隆抗体免疫对tau和Aβ病理学的影响将通过免疫化学和免疫组织化学方法进行评估。生物化学这些I期研究之后将进行II期应用，用于产生细胞系。引导具有与相应的小鼠单克隆相似或更高活性的人源化抗体，然后引导到大规模GMP生产、IND、交叉反应和非靶组织结合试验，沿着安全性研究和人体临床试验。拟议研究的成功完成将导致第一阶段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，并可能导致这些疾病的治疗和预防。在我们相信，鉴于AD的多因素性和异质性，疗法一方面，我们正在开发神经营养化合物P021，以刺激神经再生。大脑，结合tau免疫疗法，可以抑制神经变性，可以进一步增加我们的大脑，这是我们公司的长期目标。