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IL-15-Based Trifunctional Antibody-Fusion Proteins with Costimulatory TNF-Superfamily Ligands for Cancer Immunotherapy

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IL-15-Based Trifunctional Antibody-Fusion Proteins with Costimulatory TNF-Superfamily Ligands for Cancer Immunotherapy IL-15-based trifunctional antibody-fusion proteins with costimulatory TNF-superfamily ligands for cancer immunotherapy Von der Fakultät Energie-, Verfahrens- und Biotechnik der Universität Stuttgart zur Erlangung der Würde eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigte Abhandlung Vorgelegt von Nadine Beha aus Villingen-Schwenningen Hauptberichter: Prof. Dr. Roland E. Kontermann Mitberichter: Prof. Dr. Thomas Kufer Tag der mündlichen Prüfung: 14.12.2018 Institut für Zellbiologie und Immunologie Universität Stuttgart 2018 Für Sascha Table of content Abbreviations ............................................................................................................................. 1 Abstract ...................................................................................................................................... 5 Zusammenfassung ...................................................................................................................... 6 1 Introduction ........................................................................................................................ 8 1.1 Cancer immunotherapy.............................................................................................. 8 1.2 Common cytokine receptor γ-chain family .............................................................. 11 1.2.1 IL-15 in cancer immunotherapy ........................................................................... 14 1.2.2 IL-15 in therapeutic approaches .......................................................................... 15 1.3 TNF superfamily-mediated costimulation of T cells ................................................. 16 1.3.1 4-1BB and 4-1BBL ................................................................................................. 19 1.3.2 OX40 and OX40L ................................................................................................... 20 1.3.3 GITR and GITRL ..................................................................................................... 21 1.3.4 Therapeutic strategies involving the TNFSF ......................................................... 22 1.4 Targets for cancer therapy ....................................................................................... 24 1.4.1 Fibroblast activating protein ................................................................................ 24 1.4.2 Epithelial growth factor receptor ......................................................................... 25 1.5 Purpose of this study ................................................................................................ 27 2 Material ............................................................................................................................ 29 2.1 General supplies ....................................................................................................... 29 2.2 Antibodies ................................................................................................................ 29 2.3 Bacteria ..................................................................................................................... 30 2.4 Buffers and Solutions ............................................................................................... 31 2.5 Cell lines .................................................................................................................... 33 2.6 Primary human cells ................................................................................................. 33 2.7 Enzymes .................................................................................................................... 33 2.8 Instruments .............................................................................................................. 33 2.9 Kits and Markers ....................................................................................................... 34 2.10 Mice .......................................................................................................................... 35 2.11 Plasmids .................................................................................................................... 35 2.12 Primers for cloning ................................................................................................... 36 2.13 Recombinant proteins .............................................................................................. 37 2.14 Reagents and Media for bacterial culture................................................................ 37 2.15 Reagent and Media for mammalian cell culture ...................................................... 37 2.16 Software ................................................................................................................... 38 2.17 Special implement .................................................................................................... 39 3 Methods ........................................................................................................................... 40 3.1 Cloning strategy of murine homologs of tri-functional fusion proteins .................. 40 3.2 Cloning strategy of fusion proteins targeting EGFR ................................................. 40 3.3 PCR ............................................................................................................................ 41 3.4 Gel electrophoresis .................................................................................................. 41 3.5 Restriction digestion ................................................................................................. 41 3.6 Ligation ..................................................................................................................... 42 3.7 Transformation ......................................................................................................... 42 3.8 Isolation of plasmid DNA .......................................................................................... 42 3.9 Sequence analysis .................................................................................................... 43 3.10 Photometric determination of DNA concentration ................................................. 43 3.11 Mammalian cell culture ............................................................................................ 43 3.11.1 General cultivation methods ............................................................................ 43 3.11.2 PBMCs ............................................................................................................... 43 3.11.3 Isolation of regulatory T cells ........................................................................... 44 3.12 Expression and purification of recombinant proteins ............................................. 44 3.12.1 Transfection of HEK293-6E ............................................................................... 44 3.12.2 Immobilized metal ion affinity chromatography (IMAC) ................................. 45 3.13 Biochemical characterization ................................................................................... 45 3.13.1 SDS polyacrylamide gel electrophoresis .......................................................... 45 3.13.2 Size exclusion chromatography ........................................................................ 46 3.13.3 Thermal stability ............................................................................................... 46 3.14 Functional characterization ...................................................................................... 46 3.14.1 ELISA ................................................................................................................. 46 3.14.2 Flow cytometry ................................................................................................. 47 3.15 Protein stability ........................................................................................................ 53 3.15.1 In vitro serum stability ...................................................................................... 53 3.16 Animal studies .......................................................................................................... 53 3.16.1 B16-FAP lung tumor model .............................................................................. 53 3.16.2 B16-FAP solid tumor model ............................................................................. 53 3.17 Statistics ................................................................................................................... 54 4 Results .............................................................................................................................. 56 4.1 Bifunctional tumor-targeted antibody-fusion proteins ........................................... 56 4.1.1 Biochemical properties ........................................................................................ 56 4.1.2 Binding properties ................................................................................................ 58 4.1.3 Costimulatory activity .......................................................................................... 59 4.2 Trifunctional tumor-targeted antibody-fusion proteins with IL-15 and 4-1BBL ...... 60 4.2.1 Biochemical characterization ............................................................................... 61 4.2.2 Binding properties ...............................................................................................
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