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Generation and Characterization of Recombinantly Polysialylated Antibody

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Generation and Characterization of Recombinantly Polysialylated Antibody Generation and Characterization of Recombinantly Polysialylated Antibody Chen Chen A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy and the Diploma of Imperial College London Division of Cell and Molecular Biology Faculty of Natural Sciences Biochemistry Building Imperial College London Exhibition Rd London, SW7 2AZ, UK ..........For my mum and dad I hereby declare that the work described in this thesis is the result of my own independent investigation, unless otherwise stated. This work has not been previously submitted for any degree and is not being currently submitted in candidature for any other degree. Chen Chen ABSTRACT With high affinity and specificity, antibodies are now proven biotherapuetics for a wide range of diseases, such as cancer and immunological conditions. However, antibody Fc-domain mediated cross reactivity with associated side effects has hindered the development of antibody therapy in a number of applications. The development of engineered recombinant antibody fragments to address the problems seen with whole monoclonal antibodies (mAbs). Their smaller size enables rapid antigen localisation, tissue penetration and higher specificity ratios. Whereas, poor pharmacokinetics due to fast blood clearance from the circulation is an important obstacle to these small molecules, and modification of antibody fragments is required for improved tissue exposure and uptake. In order to improve protein pharmacokinetics whilst maintaining good tissue/tumour to blood ratios and low cross-reactivity, conjugation of antibody fragments with a natural polymer polysialic acid (PSA) composed by N-acetylneuraminic acid (Neu5Ac or NANA), has been investigated. Compared to polyethylene glycol (PEG) conjugation, which is the predominant approach, PSA appears to be a better alternative because it is biodegradable, non-toxic and highly hydrophilic. In this project, an anti-carcinoembryonic antigen scFv (MFE-23), and an anti-HER2 scFv (C6.5) were used as model antibody fragments to conjugate with PSA. To overcome the limitations of chemical conjugations, this project was focused on the investigation of recombinant polysialylation of single chain antibodies. ScFv genes were firstly incorporated with a naturally polysialylatable (Ig5 and FN1) domains from human neuronal cell adhesion molecule. After transfections into polysialyltransferases-expressing HEK-293 cells, the biosynthesized sialic acid was enzymatically added to the N-glycosylated fusion protein Ig5 domain for elongating the attached PSA chain. Expressed by monoclonal cell secretion, polysialylated scFvs were successfully generated and purified. Based on the negative charge of PSA, an ion exchange method was developed for separating different polysialylated scFv isoforms. The degree of polymerization (DP) was detected by mass spectrometry, which showed an average of recombinant DP of up to 20 NANA residues attached to a complex N- glycan core. Affinity binding tests by ELISA confirmed the antibody KD was significantly retained at approximately 5nM after polysialylation, however BIAcore kinetic analysis demonstrated influencing change to the KD due to the strong negative charge of PSA. In vitro - 1 - experiments using both FACS and confocal microscopy suggested that recombinant polysialylation has no affect of targeting antigens expressed on the live cell surface. Molecular hydrodynamic radius increases of polysialylated scFvs were detected by size exclusion chromatography, which led to corresponding pharmacokinetic improvement from in vivo mice studies with enhanced serum half-lives. - 2 - ACKNOWLEDGEMENTS I would like to thank my supervisor Dr. Deonarain for his great guidance, directions and support to me during my PhD research. Without you, I cannot achieve all the goals listed in my PhD aims. In addition, rather than an advisor and a teacher, Dr Deonarain is more like a friend to me. His suggestions and advice not just impacted on my research, but also influenced me in terms of being a good scientist as well as living abroad in the UK. I would also like thank Dr Jane Saffell, my co-supervisor, who supplied me with plenty information of NCAM and associated neuroscience knowledge. To the RAT lab members, I had great memory of each one of you guys during the past three and half years. Sarah, it was great to have you at the very beginning of my PhD, without you I could not find my way in the new environment quickly. Nathan and Laura, thank you very much for all the helps in the lab, and all the funs out side the lab. Ioanna and Adzima, we started almost the same time as well as finish time, and I am so glad to have you two hanging around making me not alone in the lab. I do wish to have you as my colleagues all the time. Heyley, the girl sitting on the right of me in the office always brought joys and laughters. Without you I do not know how bored I would be during my thesis writing up. Irene, thanks for your patient help with FACS demonstration; Gokhan, it is always great to have a chemistry expert in the group and Silvia, it was equally great to have you in the group towards the end of my PhD. I would also like to specifically thank Tony (Dr. Constantinou) who initiated the recombinant polysialylation work. It was also very efficient of working in the lab with you, as well as co-authorizing publications and getting pints down in the pub; Bijal, who is currently carrying on the recombinant polysialylation project with new goals to achieve, and Shuqi Wang, who was a master student, spent 6 months with me, and made breakthrough contribution on the C6.5 fusion protein polysialylation. In addition I would like to thank the entire past project students in the group, who shared the enjoyable time with me during my PhD journey. For additional technical support, I would like to thank John. Besides his excellent help in the lab, I am also very delighted to have a conversation with him about any inventive ideas (although most were not quite applicable). For the mass spectrometry work, I warmly thank Kevin, Dr. Haslem and Prof. Dell, as well as the entire mass spectrometry facility of Imperial - 3 - College for their hard work and excellent illustrations to get the MADLI-TOF MS results of PSA. I would also like to say thanks to Prof. Chester (UCL cancer institute, UK) and Prof. Colley (University of Illinois College of Medicine, USA) for their generous provides of important research materials that pushes the project forward. To my friends – Niels, you are the most reliable friend who shared the same PhD journey with me for the past years. My old mates back in China, there are no better spiritual support than you guys, and without you guys, I would not have better holidays in China. To my girl-friend, Hui, a special thank-you is for having all the lovely time we are together, and sorry for the endless thesis writing, but your belief of my success is definitely an encouragement to me. Lastly and most importantly, I would like to thank my parents who are tirelessly supporting me with their love, care, encouragement, and life-time savings. This thesis is for you! No matter how proud you are now for having a son who is probably the first Dr. educated from UK from the entire family history, I thank god to make me have parents like you, who are also my best friends all the time, and never lose any faith on me. Hopefully, this is worthy of not be with you for all these years abroad. I love you, mum and dad! I would also love to say a super special thank-you to my aunt. Without your financial support and consistent belief in me, I would not have done this much and be like what I am now. Thank you, all my families, and people helped me, loved me, and having faith of me. - 4 - Contents Abstract 1 Acknowledgements 3 Contents 5 List of Figures 10 List of Tables 16 List of Schemes 17 Abbreviations 18 Quotation 24 CHAPTER 1 ................................................................................................. - 25 - 1.1 Antibodies in Therapy ............................................................................................. - 26 - 1.1.1 Antibody – Immune system‟s powerful weapon ................................................ - 26 - 1.1.2 History of Antibody Based Therapies ................................................................ - 28 - 1.1.3 Approved mAbs for Disease Treatment ............................................................. - 31 - 1.1.4 Therapeutic Mechanisms of Approved mAbs .................................................... - 34 - 1.2 Antibody Engineering – Fragmentation and Recombinant Fusion .................... - 44 - 1.2.1 Strength and Weaknesses of the Antibody Fc Domain ...................................... - 45 - 1.2.2 Antibody Fragmentations and Recombinant Fusions ......................................... - 56 - 1.3 Modulating the Pharmacokinetics of Therapeutic Antibodies............................ - 66 - 1.3.1 Chemical Conjugation ........................................................................................ - 68 - 1.3.2 Recombinant Approaches ................................................................................... - 78 - 1.3.3 Summary of PK Modulating Approaches for Antibody Fragment .................... - 83 - 1.4 NCAM and Mammalian Polysialic Acid ............................................................... - 85 - 1.4.1 Neural Cell Adhesion Molecule ......................................................................... - 85 - 1.4.2 NCAM Polysialylation ......................................................................................
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