Pre-clinical study to fulfill FDA requirements for the completion of AV-1959 IND

临床前研究以满足 FDA 完成 AV-1959 IND 的要求

基本信息

批准号：
8887223
负责人：
Michael G Agadjanyan
金额：
$ 115.22万
依托单位：
INSTITUTE FOR MOLECULAR MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887223
关键词：
Advisory Committees Affect Althaea Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid Amyloid beta-Protein Animals Antibodies B-Lymphocyte Epitopes Biodistribution Biological Biotechnology Blood Vessels Brain Businesses Cells Cessation of life Clinic Clinical Clinical Protocols Clinical Trials Cognitive Cyclic GMP DNA DNA Vaccines Deposition Development Diagnosis Dose Drug Evaluation Edema Electroporation Epitopes Evaluation FDA approved Funding Future Generations Goals Histocompatibility Antigens Class II Human Immune Response Genes Immune response Immunologist Impaired cognition Individual Infiltration Inflammation Institutes Investigational Drugs Investigational New Drug Application Life Lymphocyte MHC Class II Genes Macaca Medical Meningeal Molecular Molecular Medicine Monkeys Mus National Institute of Neurological Disorders and Stroke Necrosis New Drug Approvals Oryctolagus cuniculus Paper Pathology Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Plasmids Publishing Recombinant DNA Recommendation Reporting Research Personnel Safety Scientist Staging System Technology Toxicology Transgenic Mice Translations United States United States National Institutes of Health Vaccinated Vaccination Vaccines autoreactive T cell base clinical efficacy cost experience extracellular immunogenic in vivo meetings mouse model multidisciplinary neuropathology novel phase 1 study phase I trial pre-clinical preclinical efficacy preclinical study programs public health relevance research study response safety study vaccine candidate

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized clinically by progressive cognitive decline, eventually resulting in death, usually within 10 years of the diagnosis. The number of demented individuals worldwide is estimated to be 35.6 million people, and it is believed that it will reach 100 million by the year 2050. According to the Alzheimer's Association, in 2013, AD will cost the United States $203 billion. This number is expected to rise to $1.2 trillion by 2050. The main goal of the proposed U01 project is a translation to the clinic of the pharmaceutical-grade DNA epitope vaccine candidate (AV-1959D) developed by our team. Recently, our team reported on generating this novel, DNA-based AD epitope vaccine composed of a short immunogenic B cell epitope of amyloid (3 copies: 3Aβ1-11), fused with a platform of multiple universal foreign Th epitopes (designated as MultiTEP) that are known to be recognized by various human immune response genes (MHC class II). Delivered by an electroporation system, the AV-1959D vaccine generates robust cellular immune responses to foreign epitopes, eliminates activation of potentially harmful autoreactive T cells and induces strong and therapeutically potent anti-Aβ antibodies in mice, rabbits, and monkeys (4 papers published). As to the cellular immune responses, AV-1959D diminished the variability of immune responses due to MHC Class II diversity, in macaques, and activated Th cells specific to epitopes from MultiTEP platform in all vaccinated animals. Accordingly, in the frame of our U44 program funded by NINDS in 2009-2012 we manufactured our leading candidate DNA vaccine, AV-1959D and completed a pre-IND meeting with the FDA in Dec of 2012. In this U01 project we propose completing the pre-clinical efficacy, safety/toxicology and biodistribution studies in APP/Tg mice (3xTg-AD) using an AgilePulseTM in vivo Electroporation system modified for mouse studies. These studies, according to FDA recommendations will be performed in two groups of 3xTg-AD mice, possessing different stages of AD-like pathology. Additionally, a safety study evaluating the affect of the vaccine on neuropathology (such as meningeal-related inflammation, microhemorrhage, vascular degeneration, vasogenic edema, etc) will be performed in Tg-SwD/I mice with extensive CAA. At the completion of these studies our multidisciplinary team, including immunologists, vaccine researchers, neuroscientists/cognitive scientists, molecular biologists, toxicologists, clinical drug developers and investigators with extensive experience in AD early and late phase clinical trials, will obtain all of the necessary regulatory documents and an FDA- approved IND for AV-1959D Phase I trials.

描述（由申请人提供）：阿尔茨海默病 (AD) 的临床特征是进行性认知能力下降，最终导致死亡，通常在诊断后 10 年内死亡。全世界痴呆症患者的数量估计为 3560 万人。相信到2050年将达到1亿。据阿尔茨海默氏症协会称，2013年美国因AD将花费2030亿美元，这一数字预计为2030亿美元。到 2050 年将增加到 1.2 万亿美元。拟议的 U01 项目的主要目标是将我们团队开发的药物级 DNA 表位候选疫苗 (AV-1959D) 转化为临床。最近，我们的团队报告了生成这种新型疫苗的情况。基于 DNA 的 AD 表位疫苗由淀粉样蛋白的短免疫原性 B 细胞表位（3 个拷贝：3Aβ1-11）组成，与多个通用外源 Th 表位（指定为AV-1959D 疫苗通过电穿孔系统产生强大的细胞免疫反应，消除潜在有害的自身反应性 T 细胞的激活，并消除潜在有害的自身反应性 T 细胞。在小鼠、兔子和猴子中诱导强效且具有治疗作用的抗 Aβ 抗体（已发表 4 篇论文）。至于细胞免疫反应，AV-1959D 减少了免疫反应的变异性。因此，在 2009-2012 年由 NINDS 资助的 U44 计划框架内，我们制造了我们领先的候选 DNA 疫苗 AV-。 1959D 并于 2012 年 12 月与 FDA 完成了 IND 前会议。在这个 U01 项目中，我们建议完成临床前功效、安全性/毒理学和使用针对小鼠研究进行修改的 AgilePulseTM 体内电穿孔系统在 APP/Tg 小鼠 (3xTg-AD) 中进行生物分布研究。根据 FDA 的建议，这些研究将在两组具有 AD 样不同阶段的 3xTg-AD 小鼠中进行。此外，还将进行一项安全性研究，评估疫苗对神经病理学（例如脑膜相关炎症、微出血、血管变性、血管源性水肿等）的影响。在具有广泛 CAA 的 Tg-SwD/I 小鼠中进行。完成这些研究后，我们的多学科团队包括免疫学家、疫苗研究人员、神经科学家/认知科学家、分子生物学家、毒理学家、临床药物开发人员。以及在 AD 早期和晚期临床试验方面拥有丰富经验的研究者，将获得 AV-1959D I 期试验的所有必要监管文件和 FDA 批准的 IND。