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Development of workflows for O-glycan profiling and structural characterisation of biopharmaceuticals

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  • Full or part time
    Prof J E Thomas-Oates
    Dr D Ungar
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

Project Description

In 2016, more than half of the top ten drugs by revenue were biologics, the majority of which are glycoproteins. The value of glycoprotein therapeutics for the pharmaceutical industry is thus clear, but this comes with a catch. The biological production of these drugs can generate batch-to-batch variability, in particular due to the non-templated biosynthesis of glycans. The glycans have important modulating effects on drug function, and they are fundamental for determining serum half-life. In order to maintain drug safety and efficacy, robust quality control methods for glycan analysis are required. In addition, cell line engineering to limit glycan heterogeneity and steer biosynthesis towards beneficial structures is needed. Glycan analysis is now routine for N-glycan profiling but methods for analysis of the second main class of protein-linked glycans, O-glycans, lag well behind, and are generally considered inadequate for industrial adoption. Routine characterisation and/or quantification of O-glycans is required to further explore the functional link with changes in O-glycan structures.

In the Thomas-Oates (mass spectrometry) and Ungar (cell biology) groups, previous shared PhD students have developed a robust combined N- and O-glycan profiling method for cultured cells (Abdul Rahman et al, J. Proteome Res., 2014, 13: 1167-1176; Skeene et al, Anal Chem 2017, 89: 5840–5849). In this IBioIC-funded PhD project the student will join the Thomas-Oates and Ungar groups, where they will build on this previous work to generate such an integrated method for glycoprotein-based biologics, which can be routinely used by CROs like industrial partner Covance, in support of future drug development projects. At the same time, cell lines with altered O-glycosylation will be generated to challenge the new method, while also producing cells with beneficial glycosylation properties. The location of Covance’s R&D laboratories close to York is a significant advantage, making frequent face-to-face visits possible. The student is expected to spend approximately one month every year at Covance, and Covance will provide expertise to help shape the proposed analytical workflows to meet industry and regulatory requirements and offer appropriate biopharmaceutical materials from the outset of the project. Through the programme, the student will gain experience in analytical carbohydrate chemistry, state of the art mass spectrometry, glycobiology, cell biology and industrial biotechnology approaches, enhancing their employability.

We encourage applications from interested applicants with a background in Chemistry, Biochemistry, or similar.

All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research.

Project-specific training will occur in the groups of the two York supervisors, and at Covance. The student will use instrumentation in the Centre of Excellence in Mass Spectrometry, where they will receive training in operation of all the relevant instrumentation; on successful completion of this training, they will use the mass spectrometers and associated peripherals (LCs, etc) to carry out their structural and quantitative analyses. Training in sample handling and MS data interpretation will be provided in the Thomas-Oates group, while in the Ungar group the student will be trained in glycobiology and cell biology techniques, and how to use them. During their placement at Covance, they will receive training in industrial biotechnological approaches.

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel:

The application deadline is 15 September, however applications will close early if a suitable candidate is found. You are therefore advised to submit your application as soon as possible.

The project will start on 1 October 2019 or as soon as possible after that date.

Funding Notes

Fully funded for 4 years by the Biotechnology and Biological Sciences Research Council (BBSRC) and Covance via the Industrial Biotechnology Innovation Centre (IBiolC). It covers: (i) a tax-free annual enhanced stipend (£16,009 for 2019-20), (ii) tuition fees at the UK/EU rate, (iii) funding for consumables. You do not need to apply separately for the funding. The studentship is available to any student who meets the UKRI eligibility criteria.

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

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