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The Evaluation of Immunogenicity of Therapeutic Antibody Drug Aggregates Using 2D and 3D in Vitro Models

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The Evaluation of Immunogenicity of Therapeutic Antibody Drug Aggregates Using 2D and 3D in Vitro Models Dissertation zur Erlangung des Doktorgrades der Fakultät Chemie und Pharmazie der Ludwig-Maximilians-Universität München The evaluation of immunogenicity of therapeutic antibody drug aggregates using 2D and 3D in vitro models Teresa Franziska Kraus aus Weingarten 2019 Erklärung Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Frau PD Dr. habil. Julia Engert betreut. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, den 01.05.2019 ____________________________ Teresa Kraus Dissertation eingereicht am: 16.05.2019 1. Gutachter: PD Dr. habil. Julia Engert 2. Gutachter: Prof. Dr. Gerhard Winter Mündliche Prüfung am: 02.07.2019 Für Opa SALUS AEGROTI SUPREMA LEX Hippokrates Acknowledgements This thesis was prepared between March 2015 and December 2018 at the Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics at the Ludwig-Maximilians-Universität München under the supervision of PD Dr. habil. Julia Engert. First and foremost, I would like to express my deepest gratitude to PD Dr. habil. Julia Engert for her excellent supervision and scientific guidance during my PhD time. I’m deeply thankful for her support and help in all research issues, the lively scientific discussions and for always having an open ear. In addition, I highly appreciated her help in preparing publications. I’m deeply grateful to Prof. Dr. Gerhard Winter for giving me the chance to work on an innovative and challenging project. I highly appreciated his outstanding scientific advice and support on a professional but also personal level. Besides the professional aims, he also attached importance to a good team spirit and always supported group activities which created an excellent working atmosphere. I would also like to thank Prof. Winter for giving me the opportunity to present my research at numerous national and international conferences. Moreover, I would like to thank Prof. Dr. Wolfgang Frieß for all the scientific discussions, his help and support in teaching matters and with organizing the ski trip as well as for the fun we had during our group activities. Together with Prof. Winter, Prof. Frieß created an outstanding working environment! This thesis would not have been possible without our collaboration partner ProBioGen AG in Berlin. Annika Lubitz, Dr. Ulrike Schließer, Dr. Christoph Giese, Jana Reuschel and Dr. Rene Brecht are deeply thanked for their support, immunological input and contribution to this thesis. I always enjoyed the lively discussions and meetings we had! Special thanks to Annika Lubitz for her help with preparing the manuscript for our publication. Moreover, I would like to thank Prof. Dr. Olivia Merkel and her group for giving me the chance to work in their cell culture lab. Dr. Aditi Mehta and Natascha Hartl are thanked for all their help and support with cell experiments. In addition, I would like to thank Andreas Stelzl for all the TRPS measurements in our joint project. My deepest gratitude is expressed to my colleagues from the research groups of Prof. Winter, Prof. Frieß and Prof. Merkel for the great time! Special thanks go to my former lab mates, Dr. Laura Engelke- Mücksch, Andreas Stelzl, Ute Rockinger and Bernard Manuel Haryadi for the great time in B.1.076! I always enjoyed the atmosphere in the big lab. Thank you “Team Solida” for being a great teaching team and for all your help and support in organizing the practical course! Not only did I meet fantastic colleagues but also friends for a lifetime! Thank you Hristo Svilenov, Andreas Tosstorff, Julian Gitter, Tobias Keil, Dr. Katharina Geh, Dr. Leticia Rodrigues Neibecker, Dr. Jacqueline Horn, Dr. Ellen Köpf, Ute Rockinger and Natascha Hartl for the fun times we had in the kitchen, at conferences, the Oktoberfest, during social activities, parties, sport events, skiing and hiking trips and travelling. It made my PhD time unforgettable and thinking of all these events makes me smile all over again! I cannot express my gratitude in words when it comes to my family. I’m deeply grateful to my parents Barbara and Josef for their unconditional love and support throughout all the years. They taught me to be self-confident and self-reliant, encouraged me to approach new challenges and supported several stays abroad which contributed substantially to my personal and professional development. I’m deeply grateful to have parents like you! I would like to thank my brother Max for his support and help and especially for his patience when pharmacy was once again the dominating topic at the family table. Moreover, I would also like to express my gratitude to my grandparents Irmgard and Hans Kremer for their love and support throughout all my life. Last, I would like to say thank you to the best partner I can imagine. Thank you Matze, for your endless and unconditional support, understanding, patience and love. You are my everything. This thesis is for my grandad Hans Kremer who passed away several years ago. He was a passioned pharmacist himself and one of the most important persons in my life. I wish he could still be with us. Table of Content General introduction ................................................................................................................... - 6 - Immunogenicity of biopharmaceuticals .............................................................................. - 7 - Induction factors of immunogenicity .................................................................................. - 7 - Clinical consequences .......................................................................................................... - 8 - Immunogenicity and protein aggregates .......................................................................... - 10 - Test models for the evaluation of immunogenicity of protein aggregates ...................... - 12 - 2D In vitro models ..................................................................................................... - 12 - In vivo models ............................................................................................................ - 14 - Conclusion and future aspects .......................................................................................... - 17 - The human artificial lymph node model ........................................................................... - 21 - Lymph nodes ............................................................................................................. - 21 - The human artificial lymph node model ................................................................... - 21 - Read-out parameters, advantages and applications of the human artificial lymph node model ................................................................................................................................... - 22 - References ......................................................................................................................... - 24 - Objectives of this thesis ............................................................................................................. - 33 - Objectives of this thesis ..................................................................................................... - 34 - References ......................................................................................................................... - 36 - Materials and Methods ............................................................................................................. - 37 - Materials ............................................................................................................................ - 38 - Monoclonal antibodies Adalimumab and Bevacizumab ........................................... - 38 - Methods used for the generation of protein aggregates.................................................. - 38 - Light stress ................................................................................................................. - 38 - Stir stress ................................................................................................................... - 38 - Heat stress ................................................................................................................. - 39 - Chemical oxidation stress using tert-butyl hydroperoxide (tBHP) ............................ - 39 - Methods used for the analysis of protein aggregates....................................................... - 39 - - 1 - Turbidity .................................................................................................................... - 39 - Light Obscuration ...................................................................................................... - 39 - Flow imaging microscopy .......................................................................................... - 40 - Dynamic light scattering (DLS) ................................................................................... - 40 - Size exclusion chromatography (SEC)........................................................................ - 40 - Protein A chromatography ........................................................................................ - 41 - Ion exchange chromatography (IEX) ......................................................................... - 41 - Fourier transform infrared spectroscopy (FT-IR) ...................................................... - 42 - Extrinsic fluorescence spectroscopy ........................................................................
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