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(MRC CASE) Understanding and predicting the immunogenicity of therapeutic protein products


Project Description

Biopharmaceuticals, or therapeutic protein products (TPPs) have been in widespread clinical use for several decades. They comprise a wide range of pharmaceutical products, from vaccines to hormones, cytokines and monoclonal antibodies. The advent of modern molecular biology accelerated their progress into the clinic, partly driven by dramatic developments in monoclonal antibody and related technologies. They are now used to treat a wide range of conditions, including malignant and inflammatory diseases. However, administration of therapeutic protein products (TPPs) in human patients over time can lead to the production of neutralising anti-drug antibodies, reducing therapeutic effectiveness and sometimes leading to adverse health effects. Such immune responses are elicited despite the fact that the administered drug is a human protein and should normally be tolerated as ‘self’ by the immune system. Future TPPs will use novel formats that do not occur in nature and potentially contain neoepitopes which could break natural immune tolerance. Consequently, regulators and industry have sought to develop methods which might predict adverse immune responses at an early stage in drug development. Our hypothesis is that changes to protein structure and aggregative state influence the way in which exogenous TPPs are recognised, internalised, processed and presented by dendritic cells. This project will focus on how antigen processing pathways in dendritic cells are modulated by changes to TPP primary and tertiary structure. Techniques employed will include biophysical analysis of TPP modification, combined with immunological studies of the responses of dendritic cells to TPP uptake by FACS, microscopy and other methods. The studentship will include an opportunity to work at the industrial sponsor, UCB, for several months.


Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This is a CASE studentship in partnership with UCB and will be funded under the MRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Supervisor to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found here View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Eyes TJ, Austerberry JI, Dearman RJ, Johannissen LO, Kimber I, Smith N, Thistlethwaite A, Derrick JP (2019) Identification of B cell epitopes enhanced by protein unfolding and aggregation. Mol Immunol 105: 181-189

Gurjar SA, Derrick JP, Dearman RJ, Thorpe R, Hufton S, Kimber I, Wadhwa M (2017) Surrogate CD16-expressing effector cell lines for determining the bioactivity of therapeutic monoclonal antibodies. J Pharm Biomed Anal 143: 188-198

Rane SS, Dearman RJ, Kimber I, Uddin S, Bishop S, Shah M, Podmore A, Pluen A, Derrick JP (2019) Impact of a Heat Shock Protein Impurity on the Immunogenicity of Biotherapeutic Monoclonal Antibodies. Pharmaceutical Research 36: 51

Ratanji K, Dearman R, Kimber I, Thorpe R, Wadhwa M, Derrick J (2016) Subvisible aggregates of immunogenic proteins promote a Th1-type response. Toxicol Sci 153: 258-270

Ratanji KD, Derrick JP, Kimber I, Thorpe R, Wadhwa M, Dearman RJ (2017) Influence of Escherichia coli chaperone DnaK on protein immunogenicity. Immunology 150: 343-355

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