Manufacturing of Drug Product, Dual Aβ/tau Vaccine for Clinical Trials

药品生产，用于临床试验的双重 Aβ/tau 疫苗

基本信息

批准号：
10667237
负责人：
Michael G Agadjanyan
金额：
$ 227万
依托单位：
INSTITUTE FOR MOLECULAR MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667237
关键词：
AN-1792 Acceleration Acetates Administrative Supplement Aducanumab Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Antibodies Antibody titer measurement Biomanufacturing Brain Budgets Buffers Clinical Clinical Data Clinical Trials Cognitive Colorado Complex Core Facility Cyclic GMP Data Dementia Development Disease Disease Progression Dose Drug Stability Early treatment Emergency Situation Engineering Environmental Risk Factor Escherichia coli Fermentation Filtration Formulation Freeze Drying Freezing Funding Goals High Pressure Liquid Chromatography Human Immunization Immunize Immunotherapeutic agent Immunotherapy Inflammation Injections Laboratories Monoclonal Antibodies Nerve Degeneration Neurofibrillary Tangles New England Onset of illness Participant Pathologic Pathology Persons Pharmaceutical Preparations Phase Phase I Clinical Trials Phosphate Buffer Physiological Populations at Risk Preparation Preventive Preventive treatment Process Production Proteins Publishing Recombinant Proteins Reporting Research Running Safety Services Testing Therapeutic Toxicology Tween 80 Universities Vaccinated Vaccination Vaccine Clinical Trial Vaccines Work abeta oligomer amnestic mild cognitive impairment analytical tool cGMP production cell bank cost disorder risk experience genetic risk factor immunogenic light scattering longitudinal analysis manufacture mouse model neuroimaging pre-clinical preclinical safety prevent programs synergism tau Proteins tau aggregation vaccination outcome vaccine trial

项目摘要

Project Summary Immunotherapy is still considered a promising therapeutic strategy for AD prevention. Data from various immunotherapeutic studies support our long-standing tenet that immunogenic AD vaccines could at least delay disease progression when they target both Aβ and Tau pathological molecules at an early stage of the disease or even in healthy people at AD risk. Recently FDA announced emergency accelerated approval of mAb Aducanumab for treatment of early AD. However, it is impractical to use very expensive mAbs as a preventive treatment for healthy subjects due to the need for frequent (monthly) administration of high concentrations (700-800mg per IV injection) of this immunotherapeutic. In contrast, almost all effective vaccines are effective when they are used as a preventive treatment. Accordingly, the major goal of the IMM-NIA cooperative U01 AG-60965 program is to manufacture single vaccines targeting tau or Aβ, and a dual vaccine, targeting both pathological molecules together. Based on this goal within the scope of the current program, we worked with Gates Biomanufacturing Facility (GBF) to manufacture two components of the dual vaccine, AV-1980R and AV-1959R recombinant proteins (drug substances), in a GMP format for first-human Phase I clinical trials. GBF developed two drug substances, AV-1980R and AV-1959R, that were tested in pre-clinical IND-enabling safety/toxicology studies. While GMP manufacturing of the first component of the dual vaccine, AV-1980R, is initiated and will be completed in August 2022, unexpectedly, technical difficulties arose with the production of the second component, AV-1959R. AV-1959R appeared to be a more aggregation-prone protein than AV-1980R, which led to a different formulation and a substantial decrease in AV-1959R production yield. While these difficulties are not significant for single vaccines, AV-1959R or AV-1980R (IND preparation is ongoing), manufacturing/formulation optimization is required for the dual vaccine prior to preparation and submission of IND. GBF team has identified a technical path forward to protein yield increase and formulation based on their experience and analytical tools such as dynamic light scattering, SDS-PAGE, and reverse-phase HPLC. Therefore, this project aims to develop a formulation for AV-1959R, which will increase the production yield of AV-1959R, support short and long-term stability, and manufacture a final cGMP grade dual vaccine (drug product). The requested funds will cover the cost of process development/formulation optimization of AV-1959R, manufacturing of cGMP AV-1959R drug substance, formulation of dual vaccine, filling/lyophilization, packaging, and release tests, stability of drug product dual vaccine.

项目概要免疫疗法仍然被认为是预防 AD 的一种有前途的治疗策略。各种免疫治疗研究支持我们长期以来的宗旨，即免疫原性 AD 当疫苗同时针对 Aβ 和 Tau 病理学时，至少可以延缓疾病进展最近 FDA 发现了这种分子在疾病早期甚至在患有 AD 风险的健康人群中的作用。宣布紧急加速批准 mAb Aducanumab 用于治疗早期 AD。然而，使用非常昂贵的单克隆抗体作为健康人群的预防性治疗是不切实际的。由于需要频繁（每月）施用高浓度（700-800mg）的受试者相比之下，几乎所有有效的疫苗都是有效的。因此，IMM-NIA 的主要目标是用作预防性治疗。 U01 AG-60965合作项目是生产针对tau或Aβ的单一疫苗，以及双疫苗，基于这一目标范围内共同针对两种病理分子。在当前计划中，我们与盖茨生物制造工厂（GBF）合作生产双疫苗的两种成分，AV-1980R和AV-1959R重组蛋白（药物 GBF 开发了两种药物，用于首次人体 I 期临床试验。 AV-1980R 和 AV-1959R 物质，已在临床前 IND 启用中进行测试在双重疫苗第一个成分的 GMP 生产过程中，进行安全/毒理学研究。 AV-1980R，启动，预计2022年8月完成，不料技术困难随着第二个组件 AV-1959R 的生产而出现，AV-1959R 似乎是一个更多的组件。与 AV-1980R 相比，易于聚集的蛋白质，这导致了不同的配方和大量的 AV-1959R 产量下降，但这些困难对于单机来说并不显着。疫苗、AV-1959R 或 AV-1980R（IND 准备工作正在进行中）、制造/配方在准备和提交 IND 之前，需要对双疫苗进行优化。已经确定了一条提高蛋白质产量和配方的技术途径经验和分析工具，例如动态光散射、SDS-PAGE 和反相因此，该项目旨在开发 AV-1959R 的制剂，该制剂将增加 AV-1959R 的含量。 AV-1959R的生产良率，支持短期和长期稳定性，并制造最终的 cGMP 级双疫苗（药品）所需资金将用于支付加工成本。 AV-1959R的开发/配方优化，cGMP AV-1959R药物的制造物质、双疫苗配方、灌装/冻干、包装和释放测试、稳定性药品双重疫苗。