Engineering TCR-like Antibodies

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 repetoires