NMR studies of liquid-liquid phase separation in biopharmaceuticals

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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.