NMR studies of liquid-liquid phase separation in biopharmaceuticals

生物制药液-液相分离的核磁共振研究

基本信息

批准号：
1782868
负责人：
金额：
--
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1782868
关键词：
NMR studies liquid phase separation

项目摘要

Protein-based biopharmaceuticals, such as monoclonal antibodies (mAbs), are quickly becoming the drugs of the future, able to treat diseases, from cancer to autoimmune disorders (1,2). The rapid development of these protein-based treatments is often hindered by the instabilities of candidate molecules, including aggregation, precipitation and liquid-liquid phase separation (3,4). Better understanding of the physical nature of such instabilities, and the ways to overcome them, would speed up the development of new drugs, eg cancer treatments. The aim of the current project, in collaboration with MedImmune, one of the world leaders in therapeutic mAbs development, is to explore the molecular mechanisms of liquid-liquid phase separation of IgG1 mAb and other proteins. The specific objectives of the project would be to study the co-solvent and temperature-dependent mechanism of liquid-liquid phase separation of mAb using NMR spectroscopy and other biophysical techniques. Solution NMR is a powerful method able to report on weak protein-excipient interactions as well as protein self-interactions, and is extremely sensitive to such parameters as rates of molecular translational and rotational diffusion: during the project the student will receive extensive training in advanced NMR spectroscopy, as well as computer-aided analysis. Moreover, through yearly month-long placements at MedImmune, the student will gain exposure to work in the industrial environment, and will be trained in industry-standard biophysical methodologies and skills such as team working and project management. The project provides an enhanced studentship and will suit an ambitious candidate with background in physics, biochemistry and/or biology.

基于蛋白质的生物药物（例如单克隆抗体（mAB））迅速成为未来药物，能够治疗从癌症到自身免疫性疾病（1,2）的疾病。这些基于蛋白质治疗的快速发展通常受到候选分子的不稳定性的阻碍，包括聚集，降水和液 - 液相分离（3,4）。更好地了解这种不稳定性的物理性质以及克服它们的方法，将加快新药的发展，例如癌症治疗。当前项目的目的与Medimmune合作，这是治疗性mABS开发的世界领导者之一，是探索IgG1 MAB和其他蛋白质液 - 液相分离的分子机制。该项目的具体目标是研究使用NMR光谱和其他生物物理技术的MAB液 - 液相分离的共溶剂和温度依赖性机理。溶液NMR是一种强大的方法，能够报告弱蛋白质优异的相互作用以及蛋白质自相互作用，并且对诸如分子平移和旋转扩散率等参数极为敏感：在项目期间，学生将接受高级NMR光谱的广泛培训，以及计算机辅助分析。此外，通过Medimmune的年度每年一个月的位置，学生将在工业环境中获得工作，并将接受行业标准的生物物理方法和技能（例如团队工作和项目管理）的培训。该项目提供了增强的学生奖学金，并将适合具有物理，生物化学和/或生物学背景的雄心勃勃的候选人。