Aggregation of Protein Therapeutics: Mechanisms, Stability, and Interdiction

描述(申请人提供)：治疗性蛋白质为许多人类疾病和状况提供了独特和关键的治疗方法，然而，如果蛋白质产品不能充分稳定，其对人类健康的好处将永远不会实现。蛋白质非常容易形成非天然的聚集体和沉淀物，这会引起患者的不良反应，从免疫反应到过敏性休克，甚至死亡。不幸的是，控制治疗性蛋白质聚集的机制还知之甚少。我们发展了一套紧密交织在一起的实验、理论和分子水平模拟来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受三个主要因素控制：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、蛋白质结构或两者兼而有之来控制。为了验证我们的中心假设，我们将使用创新的、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和蛋白质-表面相互作用。我们选择了一大套模型蛋白质，以涵盖广泛的蛋白质结构类别、相对分子质量和功能。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。生物技术研究伙伴小组将由科罗拉多大学药物生物技术中心主任Ted Randolph教授领导。该团队的主要科学人员包括：聚合物生物应用专家Kristi Anseth教授(加州大学科罗拉多分校)、治疗性蛋白质配方专家John Carpenter教授(加州大学科罗拉多健康科学中心)、蛋白质聚集计算机模拟领域的领导者Carol Hall教授、人造蛋白质生产专家Kristi Kiick教授、为蛋白质聚集分析建模的专家Christopher Roberts教授(加州大学特拉华州)，以及研究蛋白质界面行为的领导者Daniel Schwartz教授。相关性：为了提高蛋白质类药物的安全性，必须解决聚集问题。这项拟议的研究将发现聚集是如何发生的，并制定防止聚集的策略。

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.