Assessing the Behaviour of Endotoxin in Biopharmaceutical Formulations: Lowering the Likelihood of Drug-Induced Toxic Shock in Patients

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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.