Novel phage display libraries and selection technologies for the isolation of fully human antibodies for pharmaceutical applications
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1 Research Collection Doctoral Thesis Novel phage display libraries and selection technologies for the isolation of fully human antibodies for pharmaceutical applications Author(s): Weber, Marcel Publication Date: 2014 Permanent Link: Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library
2 Diss. ETH N Novel phage display libraries and selection technologies for the isolation of fully human antibodies for pharmaceutical applications A thesis submitted to attain the degree of DOCTOR OF SCIENCES (Dr. sc. ETH Zurich) presented by Marcel Weber MSc Pharm. Sciences ETH Zurich Born on April 20, 1985 Citizen of Zurich, Switzerland Accepted on the recommendation of Prof. Dr. Dario Neri, examiner Prof. Dr. Cornelia Halin, co-examiner 2014
3 Summary Therapeutic antibodies are a well-established class of protein drugs, which recognize cognate proteins with exquisite specificity and which may decrease the side effects associated to conventional therapies, especially for oncological applications. Several antibodies have received marketing authorization, especially for the treatment of cancer and of chronic inflammation, but development activities in other disease areas (e.g., osteoporosis, cardiovascular diseases, infection) are also growing. For these reasons, there is a substantial interest for the development of tools and methodologies, which facilitate the isolation and affinity-maturation of human monoclonal antibodies for pharmaceutical applications. One of the most powerful technologies for the isolation of fully human antibodies in vitro is represented by phage display technology. Several antibody phage display libraries have been described over the last two decades. In this thesis, we describe the construction and characterization of a synthetic phage display library containing over 40 billion human antibody clones in single-chain fragment variable format (scfv). The library was designed with the aim to yield binders against virtually any target protein of interest. The scfv antibody fragment format is particularly attractive for research applications, since scfvs can be produced in E.coli. We judiciously designed the antibody library based on an antibody germline VH gene, which confers to the corresponding scfv fragments the ability to binding to Protein A, thus facilitating affinitychromatography purification procedures. ScFv fragments can be easily reformatted into different antibody formats. Furthermore, the modular design of the library facilitated the implementation of affinity maturation procedures. The library has shown to be highly functional, as 90% of randomly selected clones were able to express scfvs in bacteria. Library selections were performed against more than 20 antigens, yielding specific binders in all cases. The generation and characterization of antibodies against the following biomedically-relevant antigens was studied in particular detail, in the context of this thesis. 8
4 - Antibodies against matrix metalloproteinases (MMPs) were raised using recombinant antigens produced in mammalian or bacterial cells. Some MMPs are overexpressed at the tumor site and during inflammation process, representing a good target for the development of biologicals. The isolated scfv fragments were expressed using a mammalian cell expression system, in order to achieve better folding properties. In particular, an anti MMP-3 antibody was reformatted in the small-immune-protein (SIP) format and used for ex vivo and in vivo studies in a murine model of rheumatoid arthritis. A preferential accumulation of this antibody in murine inflamed paws could be observed. - We generated a human monoclonal antibody specific to the alternativelyspliced extra-domains BCD of tenascin-c. This target is over-expressed in many malignancies, while being almost undetectable in most normal adult tissues. An extensive immuno-fluorescence analysis of the properties of this antibody is presented in the thesis. - Placental alkaline phosphatase (PLAP), an established marker of ovarian cancer, was considered to be a suitable candidate antigen for the generation of tumor-targeting antibodies. We generated two high affinity fully human antibodies against PLAP. The two antibodies recognized the native antigen in human placenta and in different cancer cell lines, as revealed by immunofluorescence and FACS experiments. Additionally, in a quantitative biodistribution study performed in tumor-bearing mice, a preferential accumulation of the antibody in the neoplastic lesions could be observed. - Using mycolactone as a target, we were able to show that the new library could be used for the successful isolation of binding specificities against complex small molecules of biomedical interest. Mycolactone is a toxin produced by the Mycobacterium ulcerans, which causes the tropical disease Buruli ulcer. Antibodies against such a toxin may be useful for inhibiting the activity of the toxin or as diagnostic tools. - We developed a novel technology for the isolation of monoclonal antibodies against integral membrane proteins. The procedure relied on the biopanning of a phage display library against a protein displayed in biotinylated nanodiscs. The methodology was successfully applied for the isolation of P-glycoproteinspecific antibodies 9
5 Zusammenfassung Therapeutische Antikörper sind mittlerweile eine anerkannte und etablierte Gruppe von Medikamenten und es ist immer noch ein wachsendes Interesse daran, neue und bessere Antikörper für medizinische Anwendungen zu finden. Eine der effizientesten Methoden um in vitro vollständig menschliche Antikörper zu finden ist Phagen-Display. Hier ist eine synthetische Antikörperbibliothek beschrieben, die mehr als 40 Milliarden verschiedene Klone enthält. Die Bibliothek besteht aus Antikörperfragmenten, sogenannten scfv die nur die variable Fragmenten eines Antikörpers miteinander verbindet. Dies erlaubt die Herstellung von stabilen und hochaffinen Antikörper-fragmente, die einfach und in grossen Mengen in Bakterien produzeiert werden können. Die ScFvs können schnell mit Protein A Chromatografie aufgereingt und zuverlässig detektiert werden durch den Myc-tag. Des weitern ist es möglich daraus diverse andere Formate von Antikörpern-fragmenten herzustellen und weitere Teile der Bindungsstelle noch affiner zu gestalten um die gesamte Affinität zu erhöhen. Die Antikörper-Bibliothek ist hoch funktional, da mehr als 90% aller Klone stabile ScFvs exprimieren und gegen mehr als 20 Antigene erfolgreich Antikörper gefunden werden konnten. In dieser Arbeit sind einige dieser Selektionen beschrieben: - Die plazentare Isoform der alkalischer Phosphatase (PLAP) ist ein Marker für Ovarialkarzinome. Antikörper gegen PLAP wurden getestet gegen die natürliche Isoform in menschlicher Plazenta sowie auf Krebszellen mit Immunofluoreszenz und in Fluoreszenz aktivierter Zell Sortierung (FACS). Auch eine Biodistribution in einer Maus mit einem xenograft tumor konnte eine Akkumulation des Antikörpers im Small-immune-protein(SIP)-Format nachgewiesen werden. - Antikörper gegen Matrix-Metalloproteinasen (MMPs) konnten isoliert werden und wurden in Bakterien und Säugerzellen exprimiert. Der Antikörper gegen MMP-3 wurde intensiv in Arthritis untersucht und es konnte eine Lokalisierung im entzündeten Gewebe nachgewiesen werden. 10
6 - Mycolactone wurde als Target genommen um zu zeigen, dass man aus der Antikörper-Bibliothek auch Antikörper gegen kleine Moleküle isolieren kann. Mycolactone ist ein Toxin des Mykobakterium ulcerans, der Erreger der tropischen Krankheit Buruli-Ulkus. Antikörper gegen ein Toxin können wirkungsvoll eingesetzt werden um den toxischen Effekt zu verhindern oder für diagnostische Zwecke. - Gegen Tenascin-C, im genaueren, gegen die alternativ gespleisste Extradomäne BCD konnten Antikörper gefunden werden, die im SIP-Format Tumorschnitte selektiv markieren konnten. - Hier beschreiben wir auch eine neue Art der Selektionen um gegen Transmembran-Proteine Antikörper zu finden. Durch Darstellung des Proteins in biotinylierten Nanodiscs konnten Antikörper isoliert werden die spezifisch für das Protein sind. 11
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Research Collection Doctoral Thesis Multiple origins of multipotent neural crest-derived cells in the adult skin Author(s): Wong, Christine Publication Date: 2006 Permanent Link: https://doi.org/10.3929/ethz-a-005284055
MehrSynthesis of 5'-C- and 2'-O-substituted oligoribonucleotide analogues and evaluation of their pairing properties
Research Collection Doctoral Thesis Synthesis of 5'-C- and 2'-O-substituted oligoribonucleotide analogues and evaluation of their pairing properties Author(s): Wu, Xiaolin Publication Date: 2000 Permanent
MehrResearch Collection. Structure-function relationships in the purified Ca-2+-pumping ATPase of plasma membranes. Doctoral Thesis.
Research Collection Doctoral Thesis Structure-function relationships in the purified Ca--pumping ATPase of plasma membranes Author(s): Zurini, Mauro Publication Date: 1983 Permanent Link: https://doi.org/10.3929/ethz-a-000311555
MehrResearch Collection. A novel biofuel cell harvesting electrical energy from activated human macrophages. Doctoral Thesis.
Research Collection Doctoral Thesis A novel biofuel cell harvesting electrical energy from activated human macrophages Author(s): Sakai Stalder, Miho Publication Date: 2009 Permanent Link: https://doi.org/10.3929/ethz-a-006020938
MehrHigh-Dimensional Gaussian and Generalized Linear Mixed Models
Research Collection Doctoral Thesis High-Dimensional Gaussian and Generalized Linear Mixed Models Author(s): Schelldorfer, Jürg Publication Date: 2011 Permanent Link: https://doi.org/10.3929/ethz-a-007018335
MehrA Methodology for Supporting Design Grammar Development and Application in Computational Design Synthesis
Research Collection Doctoral Thesis A Methodology for Supporting Design Grammar Development and Application in Computational Design Synthesis Author(s): Königseder, Corinna Publication Date: 2015 Permanent
MehrSynthetic lethal screening as a tool to identify co-dependent pathways for cancer cell survival
Research Collection Doctoral Thesis Synthetic lethal screening as a tool to identify co-dependent pathways for cancer cell survival Author(s): Helbling, Marianne Margrit Publication Date: 2010 Permanent
MehrResearch Collection. Medical Risk Communication and Decision Making: Results of Eye Tracking Studies. Doctoral Thesis. ETH Library
Research Collection Doctoral Thesis Medical Risk Communication and Decision Making: Results of Eye Tracking Studies Author(s): Kreuzmair, Christina Publication Date: 2015 Permanent Link: https://doi.org/10.3929/ethz-a-010581311
MehrSterilisation von stückigen Lebensmitteln mit Mikrowellen
Research Collection Doctoral Thesis Sterilisation von stückigen Lebensmitteln mit Mikrowellen Author(s): Spreng, Hans Publication Date: 1975 Permanent Link: https://doi.org/10.3929/ethza000119193 Rights
MehrResearch Collection. To sense or not to sense viral RNA - essentials of coronavirus innate immune evasion. Doctoral Thesis.
Research Collection Doctoral Thesis To sense or not to sense viral RNA - essentials of coronavirus innate immune evasion Author(s): Kindler, Eveline Patricia Publication Date: 2015 Permanent Link: https://doi.org/10.3929/ethz-a-010560814
MehrResearch Collection. REM-Schlafregulation der Ratte Experimente und Simulationen. Doctoral Thesis. ETH Library. Author(s): Schuller, Jan C.
Research Collection Doctoral Thesis REM-Schlafregulation der Ratte Experimente und Simulationen Author(s): Schuller, Jan C. Publication Date: 2001 Permanent Link: https://doi.org/10.3929/ethz-a-004227727
MehrCauchy-Riemann distributions and boundary values of analytic functions
Research Collection Doctoral Thesis Cauchy-Riemann distributions and boundary values of analytic functions Author(s): Straube Emil J. Publication Date: 1983 Permanent Link: https://doi.org/10.3929/ethz-a-000301590
MehrCombining Lock-Free Programming with Cooperative Multitasking for a Portable Multiprocessor Runtime System
Research Collection Doctoral Thesis Combining Lock-Free Programming with Cooperative Multitasking for a Portable Multiprocessor Runtime System Author(s): Negele, Florian Publication Date: 2014 Permanent
MehrIdentification and characterization of adult neural stem and progenitor cells ETH ZURICH
DISS. ETH NO. 18559 Identification and characterization of adult neural stem and progenitor cells A dissertation submitted to ETH ZURICH for the degree of Doctor of Sciences presented by Franz-Josef Obermair
MehrHPLC-Charakterisierung von Lektinen der Mistel (Viscum album L.) und Verbreitung der Pflanze in der Schweiz
Research Collection Doctoral Thesis HPLC-Charakterisierung von Lektinen der Mistel (Viscum album L.) und Verbreitung der Pflanze in der Schweiz Author(s): Hofstetter, Martin Publication Date: 1985 Permanent
MehrDesign, characterization and simulation of avalanche photodiodes
Research Collection Doctoral Thesis Design, characterization and simulation of avalanche photodiodes Author(s): Meier, Hektor Taavi Josef Publication Date: 2011 Permanent Link: https://doi.org/10.3929/ethz-a-006445001
MehrDie einfachste Diät der Welt: Das Plus-Minus- Prinzip (GU Reihe Einzeltitel)
Die einfachste Diät der Welt: Das Plus-Minus- Prinzip (GU Reihe Einzeltitel) Stefan Frà drich Click here if your download doesn"t start automatically Die einfachste Diät der Welt: Das Plus-Minus-Prinzip
MehrResearch Collection. On Successive Cancellation Decoding of Polar Codes and Related Codes. Doctoral Thesis. ETH Library. Author(s): Schürch, Christian
Research Collection Doctoral Thesis On Successive Cancellation Decoding of Polar Codes and Related Codes Author(s): Schürch, Christian Publication Date: 2016 Permanent Link: https://doi.org/10.3929/ethz-a-010811963
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