NMR studies of liquid-liquid phase separation in biopharmaceuticals

以蛋白质为基础的生物制药，如单克隆抗体（mab），正迅速成为未来的药物，能够治疗从癌症到自身免疫性疾病等疾病（1,2）。候选分子的不稳定性，包括聚集、沉淀和液-液相分离，往往阻碍了这些基于蛋白质的治疗方法的快速发展（3,4）。更好地了解这种不稳定性的物理本质，以及克服它们的方法，将加速新药的开发，例如癌症治疗。目前项目的目的是与世界上治疗性单克隆抗体开发的领导者之一MedImmune合作，探索IgG1单克隆抗体和其他蛋白质的液-液相分离的分子机制。该项目的具体目标是利用核磁共振波谱和其他生物物理技术研究单抗液-液相分离的共溶剂和温度依赖机制。溶液核磁共振是一种强大的方法，能够报告弱蛋白质-赋形剂相互作用以及蛋白质自身相互作用，并且对分子平移和旋转扩散速率等参数非常敏感：在项目期间，学生将接受高级核磁共振波谱学以及计算机辅助分析方面的广泛培训。此外，通过每年在MedImmune为期一个月的实习，学生将获得在工业环境中工作的机会，并将接受行业标准生物物理方法和技能的培训，如团队合作和项目管理。该项目提供了一个增强的学生，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。

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.