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Assessing the Behaviour of Endotoxin in Biopharmaceutical Formulations: towards creating improved medicines

  • Full or part time
  • Application Deadline
    Friday, November 15, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Supervisors: Dr Alexander Golovanov (The University of Manchester) and Dr Adrian Podmore (AstraZeneca)

Biopharmaceuticals are the fastest-growing type of treatments for wide range of diseases, with enormous potential for personalised medicine. Preparations of biopharmaceuticals for injections into patients should be free of contaminating endotoxin (Lipopolysaccharides, LPS), which otherwise may cause unwanted pyrogenic response and in its more severe form could lead to septic shock and death. LPS is a large amphiphilic molecule, comprised of a fatty acid component (Lipid A) and a polysaccharide component, containing phosphates and also glucosamine. This leads to hydrophilic ‘outer component’, an ionic core, and a hydrophilic ‘inner’ component; that means it can form micelles above a critical concentration (critical micelle concentration, CMC). LLPS can potentially interact with formulation components such as ions, buffers, and biopharmaceuticals themselves, which may complicate their detection and subsequent removal. The nature of specific and non-specific interactions that endotoxin monomers and micelles can have with different components of the formulation is as yet unstudied.
The proposed project is aimed at developing novel approaches for monitoring behaviour of LLPS molecules in solution, and characterising their interactions with divalent cations, chelating agents, buffers and monoclonal antibodies, and exploring the way the clusters of these molecules are formed. The findings of this project will ultimately contribute to improving speed of bringing new and safer treatments to market and lowering costs of life saving drugs.
The project will provide extensive training in advanced solution NMR techniques, LLPS chemistry and other biophysical methods, such as CG-MALS, DLS, and A4F, to obtain a comprehensive picture of inter- and intra-molecular interactions in this system. At least one month each year will be spent at placement at AstraZeneca’s site in Cambridge, to run additional experiments and obtain further experience working in Industry.

Academic background of candidates
Applicants are expected to hold, or about to obtain, a first class or upper second class undergraduate degree (or equivalent) in Biochemistry, Biophysics, Biotechnology, Chemical Engineering, Medicinal Chemistry or related discipline. A Masters degree in a relevant subject and/or experience in carbohydrate chemistry, pharmacology, protein science, structural biology, liquid state NMR spectroscopy or biopharmaceutical formulations is desirable but not essential.

Contact for further Information
Dr Alexander Golovanov,

http://www.manchester.ac.uk/research/A.Golovanov/


Funding Notes

This is a 4 year PhD BBSRC CTP studentship with AstraZeneca. Funding will cover tuition fees, stipend and consumables.

Open to UK/EU applicants with 3 years residency in the UK.

We expect the programme to commence in September 2020.

References

• Edwards JM, Derrick JP, van der Walle CF, Golovanov AP. (2018). 19F NMR as a Tool for Monitoring Individual Differentially Labeled Proteins in Complex Mixtures. Mol Pharm. 15(7), p2785-2796.
• Edwards JM, Bramham JE, Podmore A, Bishop SM, van der Walle CF, Golovanov AP. (2019). 19F Dark-State Exchange Saturation Transfer NMR Reveals Reversible Formation of Protein-Specific Large Clusters in High-Concentration Protein Mixtures. Anal Chem. 91(7), p4702-4708.
• Reich et al (2016). Masking of endotoxin in surfactant samples: Effects on Limulus-based detection systems. Biologicals 44, p417-422
• Ribi, Edgar et al. (1966). Reaction of Endotoxin and Surfactants I. Physical and Biological Properties of Endotoxin Treated with Sodium Deoxycholate. J.Bacteriol. 92 (5), p1493-1509,
• Schwarz et al (2017). Biological Activity of Masked Endotoxin. Sci Rep 7, p44750.

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