Engineering TCR-like Antibodies
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- Institutt for biovitenskap [2158]
Abstract
The aim of this thesis was to combine computational and experimental methods to engineer high affinity gluten pMHC specific antibodies, validate them, and use them to study peptide presentation in CeD patients and explore their therapeutic potential. Furthermore, the aim was to dissect the interaction between gluten pMHC and a semi-public TCR to gain new insights into CeD and T-cell repertoire forma- tion. The specific goals were: 1. Selection and characterization of antibodies specific for HLA-DQ2.5 in complex with DQ2.5-glia- 1a and DQ2.5-glia- 2 2. Characterization of gluten peptide presentation in human biopsy material using the HLA-DQ2.5:DQ2.5-glia- 1a specific antibody 3. Engineering high affinity variants of the pMHC specific antibodies for increased sensitivity using computational models and phage display 4. In vitro characterization of the high affinity antibodies regarding their speci- ficities and affinities 5. Exploring the therapeutic potential of the pMHC specific antibodies 6. Finemapping the interaction of HLA-DQ2.5:DQ2.5-glia- 2 with the prototypic antigen specific TCR to gain insights into CeD and the selection of biased antigen specific repetoiresList of papers
Paper 1: Plasma cells are the most abundant gluten peptide MHC-expressing cells in inflamed intestinal tissues from patients with celiac disease. Lene Støkken Høydahl, Lisa Richter, Rahel Frick, Omri Snir, Kristin Støen Gunnarsen, Ole JB. Landsverk, Rasmus Iversen, Jeliazko R. Jeliazkov, Jeffrey J. Gray, Elin Bergseng, Stian Foss, Shuo-Wang Qiao, Knut EA. Lundin, Jørgen Jahnsen, Frode L. Jahnsen, Inger Sandlie, Ludvig M. Sollid, Geir Åge Løset. Gastroenterology 2019 Apr;156(5):1428-1439.e10. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1053/j.gastro.2018.12.013 |
Paper 2: Engineering gliadin-specific TCR-like antibodies with picomolar affinities using docking models and phage display. Rahel Frick, Lene Støkken Høydahl, Ina Hodnebrug, Jeliazko R. Jeliazkov, Kristin Støen Gunnarsen, Shraddha Kumari, Grete Berntsen, Terje Frigstad, Erik S. Vik, Knut E. A. Lundin, Jørgen Jahnsen, Jeffrey J. Gray, Ludvig M. Sollid, Inger Sandlie, Geir Åge Løset. To be published. The paper is not available in DUO awaiting publishing. |
Paper 3: A confined TRAV26-1 encoded recognition motif focuses the biased Tcell response in celiac disease Rahel Frick, Kristin Støen Gunnarsen, Shiva Dahal-Koirala, Louise Fremgaard Risnes, Ludvig M. Sollid, Inger Sandlie, Lene Støkken Høydahl, Geir Åge Løset. To be published. The paper is not available in DUO awaiting publishing. |