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WAGNER-DISSERTATION-2017.Pdf Copyright by Ellen Kathleen Wagner 2017 The Dissertation Committee for Ellen Kathleen Wagner Certifies that this is the approved version of the following dissertation: ENGINEERING AND APPLYING NEXT-GENERATION ANTIBODY THERAPEUTICS FOR INFECTIOUS DISEASES Committee: Jennifer Maynard, Supervisor George Georgiou Lauren Ehrlich Jason Upton Lydia Contreras ENGINEERING AND APPLYING NEXT-GENERATION ANTIBODY THERAPEUTICS FOR INFECTIOUS DISEASES by Ellen Kathleen Wagner, B.S. Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin May 2017 Acknowledgements I would first and foremost like to thank my advisor, Jennifer Maynard, for her unwavering support and excellent scientific mentorship. I would not have been successful in lab without Annalee Nguyen, who taught me most of the techniques I use in lab. My labmates are some of my closest friends and scientific sounding boards, and I would not have remained relatively sane without their companionship. Finally, my committee members George Georgiou, Lauren Ehrlich, Lydia Contreras, Jason Upton, and Pengyu Ren have provided helpful feedback on my work, and encouraged my development as a scientist. Science does not exist in a vacuum, and I am humbled by my many exceptional peers in chemical engineering and other departments at UT. Their friendship and research stories are a continual reminder to always keep things in perspective. I am inspired by my fellow female scientists, and I am honored to have been a part of CHEetahs flag football and the Chemical Engineering Women’s group. To my mom, dad, and brother; thank you for teaching me to be brave, curious, hard-working, independent, and adventurous. Dad, thank you for encouraging me to look at the stars, and Mom, thank you for showing me how to get there. To my brother Paul; thank you for being a patient and positive teacher and always inspiring me to try new things. Thank you to my grandparents and extended family, who have always been kind and supportive. And finally, thank you to my dog Donovan McTwist, who doesn’t give a crap about science and makes me laugh every day. iv ENGINEERING AND APPLYING NEXT-GENERATION ANTIBODY THERAPEUTICS FOR INFECTIOUS DISEASES Ellen Kathleen Wagner, Ph. D. The University of Texas at Austin, 2017 Supervisor: Jennifer Maynard Antibodies have been engaging with infectious diseases since the evolution of cartilaginous fish, though it is only in very recent history that humans have been able to harness this expertise. The concept of using antibodies as therapeutics was first put into practice in the late 1890’s and was called serum therapy. Although this remedy was revolutionary for the treatment of virulent infections, significant side effects as well as the introduction of modern antibiotics caused a rapid decline of the practice in the 1930s. It is now 80 years later and antibodies for infectious indications are experiencing a renaissance. In particular, the evolution of antibiotic-resistant bacteria, the emergence of new pathogens, a growing population of immunocompromised individuals, and the continual search for the next cure has caused many to take a second look at antibodies. The exceptional specificity and biocompatibility of antibodies makes them agreeable therapeutics, and the invention and maturation of protein engineering has given us a toy box of new strategies for their design. In particular, next-generation formats, such as antibody mixtures, bispecific antibodies, and T-cell-receptor driven approaches, are proving useful for the treatment of infectious diseases. These new formats are able to provide broad coverage against mutable pathogens and open new therapeutic avenues by redirecting the immune system. In this dissertation I will lead you through my last 5 years of research and show you what I have learned about engineering and applying next- generation antibody therapeutics for infectious diseases. v Table of Contents List of Tables ...........................................................................................................x List of Figures ........................................................................................................ xi Chapter 1: Engineering principles and pipeline for therapeutic antibodies for infectious disease ............................................................................................1 Abstract ...........................................................................................................1 Introduction .....................................................................................................2 Engineering antibodies for infectious diseases ...............................................6 Selection of target and affinity maturation ............................................7 Improving neutralization with oligoclonal antibody mixtures.............12 Fc engineering for improved function and half-life .............................15 Designing novel antibody formats for novel methods of action ..........17 A survey of anti-infective antibodies in development ..................................20 Prophylaxis of common diseases in high-risk patients ........................24 Respiratory Syncytial Virus ........................................................24 Human Cytomegalovirus ............................................................24 Hepatitis B and Hepatitis C.........................................................25 Pertussis ......................................................................................25 Neutralization of bacterial toxin bioterrorism agents ..........................25 Anthrax .......................................................................................25 Botulism ......................................................................................26 Other bacterial toxins ..................................................................26 Treatment and prevention of healthcare-associated infections ............27 Clostridium difficile infection.....................................................27 Staphylococcus Aureus Pneumonia ............................................27 Pseudomonas aeruginosa pneumonia .........................................28 Potent neutralization of deadly viruses ................................................28 Human immunodeficiency virus - 1 ...........................................28 Influenza A..................................................................................29 vi Ebola ...........................................................................................29 Rabies ..........................................................................................30 Other emerging viruses ...............................................................30 Broad spectrum and host-mediated approaches ...................................30 Unusual cell morphology ............................................................30 Host immune regulation ..............................................................31 Conclusion ....................................................................................................32 Chapter 2: A cocktail of humanized anti-pertussis toxin antibodies limits disease in murine and baboon models of whooping cough ..........................33 Abstract .........................................................................................................33 Introduction ...................................................................................................34 Materials and Methods ..................................................................................37 Study design .........................................................................................37 Antibody variable region cloning and humanization ...........................38 Protein expression & purification ........................................................38 ELISA and binding assays ...................................................................39 In vitro neutralization ...........................................................................40 Bacterial strain and growth ..................................................................41 Ethics Statement...................................................................................41 Murine pharmacokinetic assay ............................................................41 In vivo mouse challenge ......................................................................42 Baboon challenge study .......................................................................42 Statistical Analysis ...............................................................................43 Results ...........................................................................................................44 Cloning and humanization of murine 1B7 and 11E6 antibodies .........44 Hu1B7 and hu11E6 antibodies are biochemically and biophysically similar to their murine predecessors .....................44 The binary combination of hu1B7 and hu11E6 is synergistic .............46 Hu1B7 and hu11E6 protect mice prophylactically from B. pertussis infection ...................................................................48 vii Hu1B7 and hu11E6 protect baboons therapeutically from infection by B. pertussis ..............................................................51 Discussion .....................................................................................................55
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