Aggregation of Protein Therapeutics: Mechanisms, Stability, and Interdiction

蛋白质治疗药物的聚集：机制、稳定性和拦截

• 批准号: 7922043
• 负责人: Theodore W Randolph
• 金额: $ 57.38万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922043
• 关键词: Address; Adverse reactions; Affect; Air; Alanine; Anaphylaxis; Arts; Behavior; Benzyl Alcohols; Biological; Biotechnology; Cessation of life; Charge; Chemicals; Colorado; Complement; Computer Simulation; Delaware; Dependence; Development; Diabetes Mellitus; Disease; Drug Formulations; Economics; Engineering; Equilibrium; Excipients; Exposure to; Glutamine; Goals; Growth; Health; Health Sciences; Hemophilia A; Human; Human Resources; Hydrophobicity; Immune response; Insulin; Insulin, Lispro, Human; Ionic Strengths; Kinetics; Life; Liquid substance; Malignant Neoplasms; Measures; Membrane Proteins; Methods; Modeling; Modification; Molecular; Molecular Weight; Myocardial Infarction; Particulate; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Polymers; Precipitation; Principal Investigator; Process; Production; Proteins; Recombinant Granulocyte Colony Stimulating Factor; Recombinant Proteins; Recombinants; Research; Safety; Solutions; Spectrum Analysis; Staging; Structural Protein; Sucrose; Surface; TNFR-Fc fusion protein; Testing; Thermodynamics; Tweens; Universities; anakinra; antimicrobial; base; design; driving force; human disease; improved; innovation; insight; intermolecular interaction; molecular dynamics; polyalanine; polypeptide; pressure; prevent; programs; protein aggregation; protein structure; research study; simulation; surfactant; theories; therapeutic protein

DESCRIPTION (provided by applicant): Therapeutic proteins provide unique and critical treatments for many human diseases and conditions However, if a protein product cannot be stabilized adequately, its benefit to human health will never be realized. Proteins are highly susceptible to the formation of non-native aggregates and precipitates, which can cause adverse reactions in patients, ranging from immune response to anaphylactic shock and even death. Unfortunately, the mechanisms that control aggregation of therapeutic proteins are poorly understood. We have developed a tightly interwoven set of experiments, theories, and molecular level simulations to address our central hypothesis that the kinetics and thermodynamics of aggregation of therapeutic proteins are controlled by three main factors: conformational stability, colloidal stability, and interactions with interfaces. Each of these factors can be manipulated by changing solution conditions, protein structure, or both. To test our central hypothesis, we will manipulate protein conformational stability, protein-protein intermolecular interactions, and protein-surface interactions by employing innovative, state-of-the-art experimental methods. We have chosen a large set of model proteins in order to encompass a broad range of protein structural classes, molecular weights, and functionalities. These experiments, and their interpretation, will be complemented by innovative computer simulations and theoretical frameworks aimed at understanding the mechanisms that control protein aggregation at a molecular level. The Biotechnology Research Partnership team will be led by Prof. Ted Randolph, director of the Center for Pharmaceutical Biotechnology at the University of Colorado. Key scientific personnel on the team include Prof. Kristi Anseth (U. Colorado) an expert in biological applications of polymers, Prof. John Carpenter (U. Colorado Health Sciences Center), an expert in formulation of therapeutic proteins, Prof. Carol Hall, a leader in the field of computer simulations of protein aggregation, Prof. Kristi Kiick (U. Delaware), an expert in production of artificial proteins, Prof. Christopher Roberts (U. Delaware), an expert in modeling an analysis of protein aggregation, and Prof. Daniel Schwartz, a leader in studying protein behavior at interfaces. Relevance: To improve the safety of protein-based drugs, the problem of aggregation must be solved. The proposed research will discover how aggregation occurs, and develop strategies to prevent it.

描述（由申请人提供）：治疗性蛋白质为许多人类疾病和病症提供独特且关键的治疗方法。然而，如果蛋白质产品不能充分稳定，则永远不会实现其对人类健康的益处。蛋白质非常容易形成非天然聚集体和沉淀物，这可能会给患者带来不良反应，包括免疫反应、过敏性休克甚至死亡。不幸的是，人们对控制治疗性蛋白质聚集的机制知之甚少。我们开发了一套紧密交织的实验、理论和分子水平模拟，以解决我们的中心假设，即治疗性蛋白质聚集的动力学和热力学由三个主要因素控制：构象稳定性、胶体稳定性和与界面的相互作用。这些因素中的每一个都可以通过改变溶液条件、蛋白质结构或两者来控制。为了检验我们的中心假设，我们将通过采用创新的、最先进的实验方法来操纵蛋白质构象稳定性、蛋白质-蛋白质分子间相互作用以及蛋白质-表面相互作用。我们选择了大量的模型蛋白质，以涵盖广泛的蛋白质结构类别、分子量和功能。这些实验及其解释将得到创新的计算机模拟和理论框架的补充，旨在了解在分子水平上控制蛋白质聚集的机制。生物技术研究合作团队将由科罗拉多大学制药生物技术中心主任 Ted Randolph 教授领导。团队的主要科研人员包括聚合物生物应用专家 Kristi Anseth 教授（科罗拉多州大学）、治疗性蛋白质配方专家 John Carpenter 教授（科罗拉多州健康科学中心）、Carol Hall 教授、蛋白质聚集计算机模拟领域的领导者、人造蛋白质生产专家 Kristi Kiick 教授（特拉华州大学）、蛋白质聚集分析建模专家 Christopher Roberts 教授（特拉华州大学）、和Daniel Schwartz 教授，界面蛋白质行为研究领域的领军人物。相关性：为了提高蛋白质药物的安全性，必须解决聚集问题。拟议的研究将发现聚集是如何发生的，并制定预防策略。