Biotechnology Research Partnerships Renewal: Aggregation of Therapeutic Proteins

生物技术研究伙伴关系更新：治疗性蛋白质的聚集

• 批准号: 8439790
• 负责人: Theodore W Randolph
• 金额: $ 89.91万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439790
• 关键词: Address; Adjuvant; Adsorption; Adverse effects; Agitation; Air; Binding; Biotechnology; Ceramics; Characteristics; Chemicals; Chromatography; Circular Dichroism Spectroscopy; Complement; Computer Simulation; Computing Methodologies; Crohn' s disease; Devices; Diabetes Mellitus; Disease; Dose; Drug Formulations; Energy Transfer; Exhibits; Experimental Models; Fluorescence; Fluorescence Resonance Energy Transfer; Glass; Health; Hemophilia A; Human; Image; Immune; Immune response; Kinetics; Lead; Length; Malignant Neoplasms; Medicine; Methodology; Methods; Modeling; Modification; Molecular; Molecular Conformation; Morphology; Multiple Sclerosis; Mus; Neutrons; Oils; Pathway interactions; Patients; Peptides; Polymers; Process; Property; Protein Conformation; Proteins; Pump; Research; Resolution; Rheology; Rheumatoid Arthritis; Risk; Role; Route; Safety; Seeds; Series; Silicone Oils; Site; Solutions; Somatotropin; Stainless Steel; Stress; Surface; Syringes; Techniques; Temperature; Tertiary Protein Structure; Testing; Theoretical model; Therapeutic; Water; Work; aggregation pathway; copolymer; design; human disease; immunogenic; immunogenicity; in vivo; infrared spectroscopy; insight; intermolecular interaction; light scattering; macromolecule; molecular dynamics; nanoparticle; particle; patient safety; protein aggregate; protein aggregation; public health relevance; research study; response; simulation; single molecule; synthetic protein; therapeutic protein; tool

DESCRIPTION (provided by applicant): Therapeutic proteins provide unique treatments for numerous human diseases and disorders including cancer, multiple sclerosis, hemophilia, rheumatoid arthritis, Crohn's disease and diabetes. Unfortunately, in significant fractions of patients receiving therapeutic protein products (up to 50% or higher), efficacy is lost due to immune response to the product. Immunogenicity may be stimulated by the presence of protein aggregates. In this project, we will use a hierarchical approach that uses advanced computer simulations combined with state-of-the art experiments to provide detailed, molecular-level information on the mechanisms by which protein aggregation occurs. Experiments will utilize synthetic proteins with designed chemical characteristics, model therapeutic proteins in murine models and commercial therapeutic proteins. Protein aggregates and pathways for their formation will be analyzed using a wide array of experimental techniques including single-molecule total internal reflectance fluorescence-Forster resonant energy transfer, small angle neutron scattering, small angle x-ray scattering micro-flow imaging, surface micro-rheology, chromatography, circular dichroism spectroscopy and infrared spectroscopy. A major focus of this renewal proposal will be the extension of our current work on protein aggregation in homogeneous solutions to protein aggregation that occurs due to interactions with interfaces such as those found in delivery devices (e.g., syringes, IV bags, IV lines, and delivery pumps).

描述（由申请人提供）：治疗性蛋白质为多种人类疾病和病症提供独特的治疗，包括癌症、多发性硬化症、血友病、类风湿性关节炎、克罗恩病和糖尿病。不幸的是，在接受治疗性蛋白质产品的患者中，有相当一部分（高达 50% 或更高）由于对该产品的免疫反应而丧失了疗效。蛋白质聚集体的存在可能会刺激免疫原性。在这个项目中，我们将使用分层方法，利用先进的计算机模拟与最先进的实验相结合，提供有关蛋白质聚集发生机制的详细的分子水平信息。实验将利用具有设计化学特性的合成蛋白质、小鼠模型中的模型治疗蛋白质和商业治疗蛋白质。将使用多种实验技术来分析蛋白质聚集体及其形成途径，包括单分子全内反射荧光-福斯特共振能量转移、小角度中子散射、小角度 X 射线散射微流成像、表面微流成像、流变学、色谱法、圆二色光谱和红外光谱。该更新提案的一个主要重点是将我们目前在均质解决方案中蛋白质聚集的工作扩展到由于与输送设备（例如注射器、静脉注射袋、静脉注射管和注射器）中的界面相互作用而发生的蛋白质聚集。输送泵）。