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High-performance glycoengineering of IgE antibodies


Project Description

Immunoglobulin E (IgE)-based antibodies are currently under investigation as novel immunotherapeutics for the treatment of cancer [1]. IgE is a heavily glycosylated glycoprotein, whose glycans make up more than 10% of its molecular mass [2]. Manipulating the glycan structure of IgE therefore offers a unique opportunity to improve the clinical performance of IgE-based antibodies. However, while it is clear that the number and nature of IgE glycans significantly affect the biological and pharmacological activity of IgE-based antibodies, it is not clear, how.

The Project

In this project, you will elucidate the effect of IgE glycan structure on the anti-cancer activity of IgE-based antibodies. You will chemically synthesise a set of unique glycosylation inhibitors [3] and use them in conjunction with established IgE culture systems [4] to generate defined IgE glycoforms. You will characterise your IgE glycoforms in a range of bioassays to establish relevant properties such as stability, antigen and receptor binding, IgE-mediated signalling and tumour cell killing, apoptosis, proliferation and viability. Finally, you will determine the glycan structure of your IgE glycoforms and identify the structural basis for the observed biological and pharmacological activities.

Importance

If successful, your research will lead to novel IgE-based therapeutics for anti-cancer therapy and establish a new, general strategy for the high-performance glycoengineering of therapeutic antibodies.

Training

This highly interdisciplinary project will provide training in a broad range of techniques relevant to biotechnology and bioengineering, including chemical synthesis, cell culture work and monoclonal antibody production, biological and pharmacological assays, and cutting-edge glycoanalysis. The project is particularly suited for a student with a background in chemistry or chemical biology, who wants to learn new skills in biotechnology, cell biology and bioanalytics.

Industrial Partner

The project will be carried out in collaboration with Ludger Ltd, a world-leading glycomics company, who will host the student for two 3-month placements. Ludger will provide access to their unique glycoanalytics technology for the structural characterisation of the IgE glycoforms, as well as comprehensive training in relevant experimental techniques and business-related transferable skills.

Application Deadline

Applications must be complete, including references, by 11th January 2019 at 5pm

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £17,296. Students from the EU are welcome to submit an application for funding, offers will be subject to BBSRC approval and criteria.

References

[1] Josephs DH, […] Karagiannis SN. Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling. Cancer Res. 77(5): 1127-1141, 2017
[2] Plomp R, Hensbergen PJ, […] Wuhrer M. Site-Specific N‑Glycosylation Analysis of Human Immunoglobulin E. J. Proteome Res. 2014, 13, 536.
[3] Pesnot T, Jorgensen R, Palcic MM, Wagner GK. Structural and mechanistic basis for a new mode of glycosyltransferase inhibition. Nat. Chem. Biol. 2010, 6, 321.
[4] Dodev TS, Karagiannis P, […] Karagiannis SN, Beavil AJ. A tool kit for rapid cloning and expression of recombinant antibodies. Sci. Rep. 2014, 4, 5885.

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