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Understanding and predicting the consequences of aggregation for the immunogenicity of therapeutic protein products


Faculty of Biology, Medicine and Health

About the Project

Therapeutic proteins, including monoclonal antibodies, are now widely used in the treatment of arthritis, cancer and other conditions. However, there is well-documented evidence that administration of therapeutic proteins in human patients over time can lead to the production of neutralising anti-drug antibodies, reducing therapeutic effectiveness. In particular, there is pre-clinical evidence that aggregation could be a contributory factor in generating adverse immunogenic responses. Novel or non-natural format therapeutic proteins, such as Fc fusions, can be particularly prone to aggregation but there are currently few reliable methods to predict the level and type of aggregate which is likely to cause adverse effects in patients. This project will focus on uncovering the critical sections of the antigen uptake and processing pathways within macrophages which are affected by therapeutic protein products (TPP) aggregation. In doing so, it will help to identify measurements which correlate with the impact of aggregates on immune cell functional response and improve our understanding of enhanced TPP immunogenicity. Such knowledge could ultimately feed into improved methods for prediction of TPP immunogenicity. The project is a collaboration of the university with AstraZeneca; the student will spend at least 3 months working on site at the company’s research centre in Cambridge (UK), and acquire a thorough training in immunology, as applied to the development of biotherapeutic drugs. It would suit a student with a background in Immunology, Biochemistry or Biomedical Science, with particular interests in commercially-orientated research.

Entry Requirements

Applicants are expected to hold (or about to obtain) a minimum upper second class undergraduate honours degree (or equivalent) in Biochemistry, Immunology, Biomedical Sciences or a related discipline. A Masters degree in a relevant subject and/or research experience in an area relevant to the research topic is particularly desirable. 

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. You MUST also submit an online application form - choose PhD Immunology.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/


Funding Notes

BBSRC iCASE Award with AstraZeneca. Studentship funding is for a duration of four years to commence in September 2021 and covers UK tuition fees and an annual minimum stipend (£15,609 per annum 21/22). The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a scholarship that will enable full studentship to be awarded to international applicants. This full studentship will only be awarded to exceptional quality candidates, due to the competitive nature of this funding.

References

1 Rane, S. S. et al. Impact of a Heat Shock Protein Impurity on the Immunogenicity of Biotherapeutic Monoclonal Antibodies. Pharmaceutical Research 36, doi:10.1007/s11095-019-2586-7 (2019).
2 Eyes, T. J. et al. Identification of B cell epitopes enhanced by protein unfolding and aggregation. Mol. Immunol. 105, 181-189, doi:10.1016/j.molimm.2018.11.020 (2019).
3 Ratanji, K. D. et al. Influence of Escherichia coli chaperone DnaK on protein immunogenicity. Immunology 150, 343-355 (2017).
4 Ratanji, K. et al. Subvisible aggregates of immunogenic proteins promote a Th1-type response. Toxicol. Sci. 153, 258-270, doi:10.1093/toxsci/kfw121 (2016).

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