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Biopharmaceutical aggregation

Combining experimental & computational approaches to understand, predict & control properties of biological molecules. Our infrastructure & expertise in biophysical & structural methods allows us to study molecular mechanisms of the aggregation process.

The rise in the development and approval of biotherapeutics has led to a raft of new challenges requiring solutions. One of these is the aggregation that can occur during the production of biopharmaceuticals at the volumes required for drug development and therapeutic dosing.

Examples of research at Leeds

Novel platform technologies have been developed which are capable of predicting and preventing protein aggregation:

Inducing protein aggregation by extensional flow

Leeds has generated a device which induces aggregation through the application of extensional flow (thus quantifying a candidate biopharmaceutical’s robustness to the stresses of production).
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In vivo platform for identifying inhibitors of protein aggregation

A β-lactamase tripartite fusion construct that is capable of identifying aggregation-prone sequences in the periplasm of Escherichia coli and screening for modulators of aggregation.
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Industrial engagement

Medimmune and the University of Leeds 

are collaborating on a PhD studentship which aims to investigate the role that transient excursions from the folded functional state of a protein plays in aggregation. These excursions, known as protein dynamics, will be explored by a number of techniques that include NMR, fluorescence and stopped-flow kinetic measurements. More >

In working with the University of Leeds on this project we gain access to expertise from many disciplines which is being focussed on the prediction and prevention of protein aggregation; one of the key obstacles facing the development of biotherapeutics today

Andrew Buchanan, Principal Scientist, Medimmune

UCB and the University of Leeds 

are using single-molecule dynamic force spectroscopy (DFS) methods to analyse aggregation-prone biopharmaceuticals at extremely low concentrations and to visualise the binding interface(s) that trigger aggregation. The project applies Leeds' expertise in DFS on protein complexes to provide new insight on the aggregation of Fabs supplied by UCB.

Leeds recently demonstrated that DFS can identify ‘binding hotspot’ residues key to binding affinity and therefore to aggregation propensity. This method measures the effect of a series mutations in one binding partner on the force required to dissociate the protein complex. It is analogous to the powerful phi-value analysis used to delineate protein folding mechanisms.

Key academics researching protein aggregation at Leeds