About the Project
Applications are invited for this exciting opportunity to work on a PhD in collaboration with MedImmune in the Molecular Analytical Science Centre for Doctoral Training (MAS-CDT) at the University of Warwick. Funding is available for 3 years in the first instance. The student will benefit from first class analytical facilities at Warwick and MedImmune and the requirement to complete the technical training offered by the Molecular Analytical Science MSc programme.
Project description
Protein drugs have the potential to target receptors specifically, or at least selectively, in a controlled designed fashion. They are thus a class of drugs that will be the focus of much future development. An increasing proportion of new drug registrations are monoclonal antibodies or recombinant protein therapeutics. However, proteins are comparatively complex molecules, structurally and chemically, and their manufacture and storage are often challenged by unfavourable biophysical and chemical properties. Currently, we do not have reliable methods to identify definitively the structure of the biomacromolecules in a sample. This is particularly an issue for the growing biosimilar market where the goal is to use existing data and claim it for a new product by proving the new formulation is exactly the same as the original. For small molecules this is relatively straightforward but for proteins (particularly glycosylated ones) and nucleic acids we do not have methods for this task. This project will involve developing a wide range of methods for this challenging task. The ultimate goal is a set of integrated experimental and theoretical biophysical methods to characterise definitively biomacromolecules and their complexes. Although targetted at the biopharmaceutical industry, applications are across the fields of protein and nucleic acid structure and function. The successful applicant will play a role in designing the direction of research.
Analytical methods need to be sensitive and able to detect changes in molecule quality such that the appropriate steps can be taken to optimise process conditions to mitigate these changes. Higher order structural changes in a protein or peptide solution can be a precursor to aggregation, fibril formation or functional change and adequate measurement of molecular properties will have significant benefits in Quality by Design approaches to drug development. Additionally, the ability to predict likely changes in physical stability on storage, based on subtle conformational changes, would also have benefits in process design. There a currently few sensitive (or high throughput) techniques able to assess the higher order structure (HOS) properties of proteins in excipient-containing solutions and most require some amount of sample processing especially when formulation concentration are high.
This project aims to establish new suitable analytical methods able to gain HOS information from drug substances. In particular Raman Spectroscopy (Raman, Raman Optical Activity and perhaps other Raman techniques) offers a sensitive alternative to circular dichroism (CD) and FTIR absorbance for measuring subtle changes in HOS. Challenges include identifying subtle structure changes, chemical changes, post translational modifications, and assembly/aggregations state identification. The aim of the project is to establish a complementary suite of techniques that for different types of biopharmaceutical with different formulations can be used for characterisation and quality control of biopharmaceutical protein and nucleic acid products. It is anticipated that the roles that techniques including: flow-CD, cryo-electronmicroscopy, optical microscopy and linear dichroism could play will be explored. The ultimate goal is a routine approach to quality by design, rather than the current quality confirmation after design approach.
The project fits into 3 themes of the MAS-CDT:
• New techniques for Quality by Design: pharmaceutical, biopharma., agro-science, personal care
• Characterising and exploiting functional biomolecular assemblies
• Advanced quantitative analysis
Research challenges will include:
• Definitive molecular characterisation of products in real time, rapid and sensitive functionality testing on/in-line.
• Structure and function of biomolecules and assemblies: harnessing nature’s methods.
• Extracting all useful information from complex data sets.
The successful candidate will benefit from the cross-discipline research community of the CDT including attendance at the annual conference and regular seminar series.
Closing date: Applicants will be considered until the position is filled.
To apply: Please apply to the MAS-CDT via http://www2.warwick.ac.uk/study/postgraduate/apply/howto/
Queries: Please contact Alison Rodger on [Email Address Removed]
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