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The Effects of Flow on Therapeutic Protein Aggregation

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The Effects of Flow on Therapeutic Protein Aggregation The Effects of Flow on Therapeutic Protein Aggregation Leon Fitzroy Willis Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds Astbury Centre for Structural Molecular Biology School of Molecular and Cellular Biology September 2018 This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. © Leon Fitzroy Willis and the University of Leeds i Statement regarding inclusion of published work in this thesis The candidate confirms that the work submitted is his/her own, except where work which has formed part of jointly-authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others: Chapters 3 and 4 "Characterising protein aggregation induced by extensional flow" include work published in the following publication: Dobson, J., Kumar, A., Willis, L.F., Tuma, R., Higazi, D.R., Turner, R., Lowe, D.C., Ashcroft, A.E., Radford, S.E., Kapur, N. and Brockwell, D.J., 2017. Inducing protein aggregation by extensional flow. Proceedings of the National Academy of Sciences, 114 (18), 4673-4678. Chapter 4 "Mapping the aggregation landscapes of proteins under defined fluid fields" includes work from the following publication: Willis, L.F., Kumar, A., Dobson, J., Bond, N., Lowe, D., Turner, R., Radford, S.E., Kapur, N. and Brockwell, D.J., 2018. Using extensional flow to reveal diverse aggregation landscapes for three IgG1 molecules. Biotechnology and Bioengineering, 115, 1216–1225. In Dobson et al. 2017 Proc. Natl. Acad. Sci., The author contribution reads: “ J.D., A.K., L.F.W., A.E.A., S.E.R., N.K., and D.J.B. designed research; J.D., A.K., and L.F.W. performed research; R. Tuma, D.R.H., R. Turner, and D.C.L. contributed new reagents/analytic tools.; J.D., A.K., L.F.W., R. Tuma, D.R.H., R. Turner, D.C.L., A.E.A., S.E.R., N.K., and D.J.B. analyzed data; and J.D., A.K., L.F.W., A.E.A., S.E.R., N.K., and D.J.B. wrote the paper.” In Willis et al. 2018, Biotechnol. Bioeng. I prepared the vast majority of the protein samples ahead of stress in the flow device. I co-performed the vast majority of the flow stress experiments with A Kumar (joint-first author). I performed the vast majority of the pelleting assays, with A Kumar measuring the A280 of the vast majority of samples following overnight incubation. I performed the vast majority of the final analysis of the data, in addition to the writing of the manuscript (submitted as part of Year 3 Draft Paper and Thesis Plan in FBS). J Dobson helped conceive the study. All authors contributed to the writing of the final manuscript. ii Acknowledgements Firstly, I would like to thank my supervisory team, Dr David Brockwell, Prof Nikil Kapur and Prof Alison Ashcroft, for their guidance and encouragement of me over the past four years and hopefully, the years to come. I also wish to thank Professor Sheena Radford for her help and tutelage despite not formally being part of my supervisory team. Secondly, I wish to thank the EPSRC Centre for Doctoral Training in Emergent Macromolecular Therapies for funding my studentship. In particular, I wish to thank Professor Paul Dalby and the other academics in the Department of Biochemical Engineering at UCL, who have introduced me to a field I did not know existed before my PhD, of which I now feel proud to be part of. I wish to thank the friends I made during my training events for making this experience as enjoyable as possible. I also wish to thank MedImmune LLC and Adimab LLC for providing additional funding, materials and advice over the last four years. Without this, most of the work in this thesis would not exist. I particularly wish to thank Drs David Lowe, Richard Turner, Nick Bond and Paul Varley (MedImmune) and Drs Tushar Jain, Yingda Xu and Max Vasquez (Adimab). Thirdly, I wish to thank Drs John Dobson and Amit Kumar for their endless help, advice and friendship. As the original ‘squishing team,’ it’s been great to get this project off the ground with you. I wish to thank all members of the Radford and Brockwell groups, past and present, for not just being great colleagues, but also great friends. I must also thank the lab manager, Mr G Nasir Khan, who always makes time for you despite his busyness! I wish to thank Drs Nuria Benseny- Cases, Sophie Goodchild, Esther Martin, James Ault and Iain Manfield for offering their time and advice to teach me many practical techniques throughout my PhD. Finally, I wish to thank my past teachers who always encouraged me to aim higher. Thanks also to all my friends and family for their timeless support and encouragement- without you I would not have written this thesis! I particularly wish to thank my parents, Debbie and Fitzroy, their respective partners Chris and Tricia, and my grandparents Janet and Roy Wilson, as they have all made me the man I am today. I dedicate this thesis to my late grandparents, Iris and Fred Willis, who I hope would be proud. At this point people usually thank their other half… As my luck has not stretched that far, I think I will end the sentiment here and talk instead about science! iii Abstract To date, over 70 monoclonal antibody (mAb) biopharmaceuticals have been approved, allowing effective treatment of serious diseases such as cancer. In addition to improving human health, these powerful medicines are very valuable, generating billions of dollars in sales annually. Like all proteins, environmental changes can cause mAbs to unfold, misfold and aggregate. Aggregation can block the progress of mAbs to market, as aggregates have been linked to adverse effects in patients. The hydrodynamic forces mAbs encounter during their manufacturing process have long been thought to be one of the causes of aggregation. This link remains tenuous, however, partly due to a lack of knowledge surrounding how specific flow fields (e.g. shear and extensional flows) perturb protein structure. To assess the effects of flow on therapeutic protein aggregation, a recently developed, bespoke Extensional Flow Device (EFD) was characterised, which mimics the hydrodynamic forces mAbs encounter at manufacturing scale. In this thesis, the model proteins BSA and three mAbs (WFL, mAb1 and STT) were subjected to the defined fluid fields present in the EFD, with the resulting aggregates characterised using an array of biophysical techniques. The data show that protein aggregation can be induced by extensional flow. The extent of aggregation depends on a protein’s sequence and topology, in addition to the flow conditions and buffer composition. For example, the mAbs WFL and STT show disparate aggregation behaviour following hydrodynamic stress, despite having >99 % sequence identity, with the generic mAb1 somewhere in between the two. Reinforced by data from a screen of 33 clinically relevant mAbs, the data in this thesis support future use of the EFD to: explore flow-induced protein aggregation mechanisms; improve mAb bioprocessing and; screen mAb candidates to select sequences and/or formulations which are resistant to potentially deleterious hydrodynamic forces, facilitating the development of next-generation mAb therapeutics. iv Table of Contents Contents Statement regarding inclusion of published work in this thesis ..................................ii Acknowledgements .................................................................................................. iii Abstract ................................................................................................................... iv Table of Contents .................................................................................................... v List of Tables ........................................................................................................... x List of Figures .......................................................................................................... xi List of Abbreviations .............................................................................................. xvi 1. Introduction ....................................................................................................... 1 1.1 Protein folding, misfolding and aggregation ............................................... 1 1.2 Introduction to biopharmaceuticals ............................................................ 4 1.2.1 . Biological molecules as therapies: A revolution in modern medicine . 4 1.2.2 Monoclonal antibodies (mAbs): The dominant products in the biopharmaceutical arena................................................................................... 5 1.2.3 Biochemical engineering: Selection, expression, purification and formulation of therapeutic antibodies .............................................................. 12 1.2.4 ‘The aggregation problem’ in the biopharmaceutical industry............ 22 1.2. Techniques used to study biopharmaceutical aggregation ....................... 26 1.3.1 In silico predictors of aggregation-prone regions .................................... 26 1.3.2. Spectroscopic and spectrometric techniques to probe higher-order structure ......................................................................................................... 29 1.2.3. Separation-based methods to probe biopharmaceutical aggregation. 37 1.2.4. Light
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