Mapping aggregation-prone regions induced by extensional flow

protein aggregation is highly problematic to the £200bn biopharmaceutical industry as it can pose dangers to the patient (loss of efficacy of the protein drug and induction of the immune response) and can increase time-to-market and, therefore, cost of goods. Over the last four years, we have shown that fluid-driven forces can drive the aggregation of model proteins such as bovine serum albumin (BSA) and biopharmaceuticals including G-CSF and those based on IgG1 scaffolds. For BSA we showed that the hydrodynamic forces exerted can cause the exposure of a new protein surface with greater self-affinity, leading to aggregation. The flow induced aggregation pathway(s) of IgGs remain unexplored and consequently industry cannot reliably identify sequences that are inherently manufacturable. As antibody drug conjugates, next generation bi-specific platforms and gene therapy vectors are already posing an even greater manufacturing challenge, aggregation remains the major threat to the realisation of the enormous potentials of proteins in the bio-technology industry.
The goal of this BBSRC CTP PhD studentship between the Astbury Centre for Structural and Molecular Biology and Medimmune, therefore, is to apply Leeds' unique expertise in protein (un)folding mechanisms, analytical mass spectrometry and hydrodynamic flow to identify the aggregation interfaces of Medimmune propriety biopharmaceuticals. This fundamental study will ultimately facilitate the economic production of current and next generation high-value bio-pharmaceuticals.