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Identifying and modulating aggregation propensity in bio-pharmaceuticals

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  • Full or part time
    Dr D Brockwell
    Prof S E Radford
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

This project is a collaboration between academics in Leeds with expertise in protein aggregation and (un)folding mechanisms and UCB Celltech - a large global biopharmaceutical company.

The UK is a major stakeholder in biopharmaceutical development and production, a sector that had sales of £105 billion in 2012. Bio-pharmaceuticals (biologics) offer major therapeutic advantages (high affinity and biocompatibility) over conventional small molecule drugs but nonetheless, pose enormous challenges in their development, production, formulation and storage. A major hurdle to be overcome is the reversible or irreversible self-association (aggregation) of biologics resulting in the failure of promising candidate biologics even at very late stages in the development pipeline. The ability to identify sequences likely to aggregate either inherently or during production, transport or storage is of crucial importance to the biologics industry, yet is currently beyond our capability.

An in vivo selection method has been developed at Leeds to quantify the aggregation propensity of single chain Fv (scFv) variants of bio-pharmaceuticals. In this project you will assess the potential of this method to rank candidates for the development/formulation of a large number of antibodies developed by UCB which also have detailed bio-physical data. This will allow any correlations between aggregation propensity and standard biophysical analyses (if any) to be identified.

If successful, this screen could revolutionise the landscape for the sector, especially in the application of complex systems such as antibodies. The ability to reliably predict bioprocessability removes a bottleneck in biologic development, facilitating commercialisation. The complementary team is assembled from academia and a large biopharmaceutical company and is thus ideally placed to undertake a feasibility study of this nature.

Training in the in vivo assay, directed evolution, protein expression, purification and biophysics will take place in Leeds; UCB Celltech will provide training in antibody engineering and protein production at an industrial scale. The excellent working relationships in the supervisory team will ensure that you make the very best of every opportunity within the academic sector and at UCB Celltech.

The placement at UCB will be timed to ensure that the training opportunities and scientific benefits of the visits are maximised.




Funding Notes

BBSRC White Rose Mechanistic Biology DTP CASE 4 year studentship.

Studentships covers UK/EU fees and stipend (c.£14,553) for 4 years to start in Oct 2018. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.

References

An in vivo platform for identifying inhibitors of protein aggregation. Saunders, J., Young, L., Mahood, R., Jackson, M., Revill, C., Foster, R., Smith, A., Ashcroft, A., Brockwell, D. and Radford, S. (2016) Nat Chem Biol. 12:94-101.

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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