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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' 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

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 阿尔茨海默氏病（AD）是美国第六大死亡原因。近600万美国人 患有广告的痛苦，其医疗保健费用近3000亿美元。目前，没有有效的治疗 可以使用这种疾病。如果未发现可以抑制，预防或治愈该疾病的治疗 到2050年，案件将三倍。这是迫切需要为AD开发有效的治疗方法。广告是 组织病理学的特征是出现了许多Aβ斑块和神经纤维缠结的缠结 交替地在大脑中过度磷酸化的tau。高磷酸化tau的tau病理也是一个标志 几种相关神经退行性疾病的病变，称为tauopathies。 tau病理的密度，而不是 Aβ斑块与AD患者的痴呆程度相关。对该领域的信念越来越 可能需要清除Aβ或TAU病理学才能成功治疗AD。到目前为止，没有 人类临床试验中使用的抗体具有这种活性。我们已经产生了几个高亲和力的tau 小鼠单克隆抗体，其中一种是tau抗体43d对人tau 6-18，不仅可以清除tau 病理学但Aβ病理学并挽救了3xTG-AD的转基因小鼠模型的认知障碍 AD和TAUOPATHY。我们建议进一步开发这种独特的tau抗体，以进行AD和相关的免疫疗法 状况。 PI已获得43D专利用于治疗AD和相关神经退行性疾病。这 SBIR I期应用的具体目的是（1）研究Tau​​小鼠单克隆的人性化 抗体43d和77E9和（2）研究人源化抗体的免疫疗法活性 与用AD PTAU处理的3XTG-AD转基因小鼠中的相应小鼠单克隆相比。 没有任何Aβ和TDP43的高磷酸化tau（PTAU）将从AD冷冻的AD型AD中分离出来 大脑，用于诱导tau播种并在3xtg-ad小鼠中散布，将用人源化进行免疫 与Aβ阴性有效的Tau抗体77E9与Tau 184-195和相应的小鼠相比，43d 单克隆。 TAU和Aβ病理免疫的影响将通过免疫组织化学和 生化。这些阶段研究将随后在生成细胞系的生成的II期应用之后 引导人性化抗体具有与相应小鼠单克隆相似或更高活性的抗体，然后领先 进行大规模的GMP制造，IND和交叉反应和非目标组织结合的测试 安全研究和人类临床试验。拟议研究的成功完成将导致第一阶段 健康志愿者和II期的人类临床试验，然后在AD和相关的III期人类临床试验中进行 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，我们认为鉴于其多因素性质和异质性，AD可能需要组合 治疗。一方面，我们正在开发神经营养化合物P021，以刺激 大脑将其与可以抑制神经变性的TAU免疫疗法结合起来，可以进一步增加我们的 成功，是我们公司的长期目标。