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Targeting the Terminal Pathway in Complement – Driven Disease

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Targeting the Terminal Pathway in Complement – Driven Disease Targeting the Terminal Pathway in Complement – Driven Disease. Wioleta Milena Zelek A thesis submitted to Cardiff University in candidature for the degree of Doctor of Philosophy. September 2019 1 Choose a job you love, and you will never have to work a day in your life. - Confucius 1 2 ACKNOWLEDGEMENTS; I would like to express my deepest thanks to the following people: • My primary supervisor Professor Paul Morgan for taking me on a journey of Complement, for his encouragement, direction and much appreciated motivating discussions throughout my PhD, all the inspiring quotes such as; “it’s only impossible until someone does it” “an expert is someone who knows almost everything about almost nothing” “…you answered one question, now there are two more to ask” “choose your battles!” • My PhD co-supervisor Professor Philip Taylor, for his inspiring comments. • Professor Claire Harris for her much valued advice, and extensive expertise during the SPR analysis, for her encouragement and ongoing support. • My PhD Annual Review panel for valuable feedback during the course of this study. • Collaborators for providing crucial reagents for this project; F. Hoffmann-La Roche Ltd., Complement Pharma, GSK, David Kavanagh and Brigitta Stockinger. • Grant Funders; Welsh Government and Life Science Research Network in Wales (LSRN) for supporting this work, LSRN Translational Support Fund for sequencing the antibodies developed and Systems Immunity Research Institute for funds to visit Monash University. • Travel award funders (British Society of Immunology and WM Thomas Fund) and conference organisers (Complement UK, ICW, EMCHD, BSI and I&I) for all the opportunities to present my data. • My industrial supervisors in particular Ms Nikki Robinson from BBI Group for the provided training that have accustomed me to laboratory SOPs; the Senior Scientist job helped me develop skills essential for success of this project. • My MSc supervisors; Professor J. Zaleski and B. Zarychta and teachers; Kusykowie and Swiechowie for their enormous support, especially Jadwiga who has been my great inspiration for many years. • Dr Michelle Dunstone and Dr Brad Spicer for hosting me at Monash University, introduction to cryo-EM and providing a friendly and enjoyable environment whilst on placement. • Complement Biology Group members for interesting presentations and helpful discussions over this work. • My family and friends for their love, encouragement and continues support, a special thanks to my sisters for all the uplifting moments and for putting up with my science talk. I dedicate this Thesis to Marian, memory of you shall never pass away. It has been a pleasure and a great opportunity to be a part of the BPM Group, I have enjoyed my PhD, and the experience and knowledge I have gained will take me forward into my future complement adventures. 3 Published papers during this PhD 1. Zelek, W. M., Xie, L., Morgan, B. P., & Harris, C. L. (2019). Compendium of current complement therapeutics. Molecular Immunology, 114, 341–352. https://doi.org/10.1016/j.molimm.2019.07.030 2. Zelek, W. M., Taylor, P. R., & Morgan, B. P. (2019). Development and characterization of novel anti-C5 monoclonal antibodies capable of inhibiting complement in multiple species. Immunology, 157(4), 283–295. https://doi.org/10.1111/imm.13083 3. Zelek, W. M., Harris, C. L., & Morgan, B. P. (2018). Extracting the barbs from complement assays: Identification and optimisation of a safe substitute for traditional buffers. Immunobiology, 223(12), 744–749. https://doi.org/10.1016/j.imbio.2018.07.016 4. Zelek, W. M., Stott, M., Walters, D., Harris, C. L., & Morgan, B. P. (2018). Characterizing a pH-switch anti-C5 antibody as a tool for human and mouse complement C5 purification and cross-species inhibition of classical and reactive lysis. Immunology, 155(3), 396–403. https://doi.org/10.1111/imm.12982 5. Kopczynska, M., Zelek, W. M., Vespa, S., Touchard, S., Wardle, M., Loveless, S., Morgan, B. P. (2018). Complement system biomarkers in epilepsy. Seizure, 60, 1– 7. https://doi.org/10.1016/j.seizure.2018.05.016 6. Zelek, W. M., Watkins, L. M., Howell, O. W., Evans, R., Loveless, S., Robertson, N. P., Morgan, B. P. (2019). Measurement of soluble CD59 in CSF in demyelinating disease: Evidence for an intrathecal source of soluble CD59. Multiple Sclerosis, 25(4), 523–531. https://doi.org/10.1177/1352458518758927 7. *Kopczynska, M., *Zelek, W., Touchard, S., Gaughran, F., Di Forti, M., Mondelli, V., Morgan, B. P. (2019). Complement system biomarkers in first episode psychosis. Schizophrenia Research, 204, 16–22. https://doi.org/10.1016/j.schres.2017.12.012 (*equal first author) 8. Boshra, H., Zelek, W. M., Hughes, T. R., Rodriguez de Cordoba, S., & Morgan, B. P. (2018). Absence of CD59 in Guinea Pigs: Analysis of the Cavia porcellus Genome Suggests the Evolution of a CD59 Pseudogene. Journal of Immunology, 200(1), 327–335. https://doi.org/10.4049/jimmunol.1701238 Papers in press; 1. Zelek, W. M., Fathalla, D., Morgan, A., Touchard S., Loveless S., Tallantyre E., Robertson N.R., Morgan B. P. Cerebrospinal Fluid Complement System Biomarkers in Demyelinating Disease. (Manuscript submitted to Multiple Sclerosis, in revision). 4 LIST OF ABBREVIATIONS GPI Glycosylphosphatidylinositol AAV Anti-neutrophil cytoplasmic HAE Hereditary angioedema antibody (ANCA)-associated HBS HEPES buffered saline vasculitis HS Hidradenitis suppurativa AChR Acetylcholine Receptor HU Huntington's Disease AD Alzheimer’s disease IgAN IgA nephropathy AKI Acute kidney injury IgG Immunoglobulin G AMD Age-related macular IgM Immunoglobulin M degeneration I/R Ischemia/reperfusion AMR Antibody-mediated K+ Potassium ion rejection KO Knockout APS Antiphospholipid syndrome KT Kidney transplant AP Alternative pathway MN Membranous nephropathy APB Alternative pathway buffer MS Multiple sclerosis aHUS Atypical haemolytic uremic mAb Monoclonal antibody syndrome MAC Membrane attack complex BSA Bovine serum albumin MASP Mannose associated serine βME Beta mercaptoethanol protease Ca2+ Calcium ion MBL Mannose Binding Lectin C3aR C3a receptor MCP Membrane co-factor protein C5aR C5a receptor Mg2+ Magnesium ion C3G C3 glomerulopathy MW Molecular weight CFD Complement fixing diluent Na+ Sodium ion COPD Chronic obstructive NMO Neuromyelitis optica spectrum pulmonary disease disorder CR1 Complement receptor 1 NMR Nuclear magnetic resonance CVF Cobra Venom Factor OmCI Ornithodoros moubata CV Column Volumes complement inhibitor CSF Cerebrospinal fluid PAGE Polyacrylamide gel electrophoresis DAF Delay accelerating factor PBS Phosphate buffered saline DDD Dense deposit disease PG Pyoderma Gangrenosum DGF Delayed graft function PD Parkinson’s Disease DMSO Dimethyl Sulphoxide PNH Paroxysmal nocturnal DNA Deoxyribose Nucleic Acid hemoglobinuria DSA Donor specific antibody RA/OA Rheumatoid arthritis/Osteoarthritis ECL Enhanced RA Rheumatoid Arthritis chemiluminescence RaCI Rhipicephalus appendiculatus ECM Extracellular matrix complement inhibotor EDTA Ethylene diamine tetra- RBC Red blood cell acetic acid RL Reactive lysis EGF Epidermal Growth factor RPE Retinal pigment epithelium EGTA Ethylene glycol-bis (ß- SCR Short consensus repeat aminoethyl SDS Sodium Dodecyl Sulphate ether) tetra-acetic acid VIII SEM Standard error of the mean EAMG Experimental autoimmune SIRS Systemic inflammatory response myasthenia gravis Syndrome ELISA Enzyme linked SLE Systemic lupus erythematosus immunosorbent assay sMAC Soluble MAC FACS Fluorescence activated cell SNP Single nucleotide polymorphism sorter SPR Surface Plasmon Resonance Fab Fragment antigen binding TCC Terminal complement components FB Factor B TED Thioester domain FD Factor D TMA Thrombotic microangiopathy FH Factor H TRIS Tris (Hydroxymethyl) methylamine FITC Fluorescein Isothiocyanate UV Ultra Violet GA Geographic atrophy wAIHA Warm type autoimmune hemolytic GBS Guillain-Barré syndrome anemia gMG Generalized myasthenia wAMD Wet AMD gravis WT Wild type 5 LIST OF FIGURES Figure 1.1 Cascade of complement activation pathways; classical, lectin and alternative, leading to MAC generation. Figure 1.2 Schematic of MAC formation showing sequential complement TP component binding to form the lytic pore. Figure 1.3 MAC visualisation using past and current technique. Figure 1.4 Cryo-EM structure of MAC. Figure 1.5 Structure of native anchored CD59. Figure 1.6 Inhibition mechanism of MAC formation by CD59. Figure 1.7 Complement implication in various diseases. Figure 2.1 Structure diagram of Integra flask. Figure 3.1 Example chromatograms of purification using affinity column, gel filtration and ion exchange chromatography. Figure 3.2 Protein characterisation using SDS-PAGE, WB, haemolysis assay and ELISA. Figure 3.4 Haemolysis assays with human C5 RO7112689-purified. Figure 3.5 Purification and Characterisation of CVF. Figure 3.6 Characterisation of C5b6 generated using purified components. Figure 3.7 Characterisation of C5b6 generated from C789D serum. Figure 3.8 Characterisation of C5b67using purified components Figure 3.9 Characterisation of sC5b-9 using purified components. Figure 3.10 Example chromatogram and SDS-PAGE of mAb purification on Protein G. Figure 4.1 Screening Assays for mAb detection. Figure 4.2 SDS-PAGE of the purified mAb 4G2, 7D4, 10B6. Figure 4.3 Haemolytic assays to investigate whether the anti-C5 mAb 4G2, 7D4, 10B6 inhibit complement mediated lysis across species. Figure 4.4 Direct and sandwich ELISA to determine 4G2, 7D4 and 10B6 binding to human and rat C5 and competition with commercial mAb. Figure
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