Bispezifische Antikörper zur Therapie der Epidermolysis bullosa acquisita
Zusammenfassung der Projektergebnisse
In the project titled "Bispecific Antibodies for Treating Autoimmune Disease Epidermolysis Bullosa Acquisita," our primary objective was to develop and evaluate bispecific T cell engagers (BiTEs) with the ability to selectively target and eliminate specific B cell subsets or antigen-specific B cells. To achieve this, we chose epidermolysis bullosa acquisita (EBA) as the model disease. EBA is a chronic inflammatory autoimmune disease that results from autoantibodies targeting type VII collagen (COL7) and causing organ-specific damage. In the immunization-induced EBA mouse model, clinical disease manifestation relies on the presence of antigen-specific T- and B-cells. In line with this, our first aim was to create BiTEs that can deplete either the COL7-specific B cells or all CD19+ B cells. To facilitate the development of these BiTEs, we established a collaboration with Matthias Peipp from the Division of Antibody-Based Immunotherapy at Christian Albrechts University in Kiel. This new cooperation was enabled by the Cluster of Excellence 2167. Here, we successfully generated both the COL7xCD3 BiTEs and the CD19xCD3 BiTEs in sufficient quantities and purity. The second objective of our study was to conduct functional in vivo testing of the generated BiTEs. We successfully completed the testing for the CD19xCD3 BiTEs, which resulted in an almost complete and sustained depletion of B cells in various immunological compartments in healthy mice. Based on these results, we proceeded to evaluate the therapeutic application of the CD19xCD3 BiTEs in the immunization induced EBA mouse model. However, contrary to our expectations, the application of the CD19xCD3 BiTEs did not lead to the depletion of CD19+ B cells, even at 10-fold higher doses. Additionally, we observed a significant decrease in T cells following treatment with the CD19xCD3 BiTEs. We assume that the adjuvant-induced expansion of B cells might lead to T cell exhaustion, ultimately rendering the CD19xCD3 BiTEs ineffective in this model. Thus, the observed effects appear to be primarily model-dependent, and not due to a lack of the presumed mode of action of the BiTEs. Due to various challenges encountered during the animal experimentation process, we have not yet been able to perform the in vivo evaluation of the COL7xCD3 BiTEs and their therapeutic application. However, to address this, we established a collaboration with Kyle Amber from Rush University in Chicago, USA. At his laboratory, we helped to set up the immunization-induced mouse model, and the experiments to test the COL7xCD3 BiTEs will commence shortly. In summary, since the commencement of the funding, we successfully accomplished most of initially set aims, except for testing the main therapeutic target in vivo for safety and potential therapeutic efficacy. This is due to several challenges during the animal experimentation. We have now overcome these obstacles by establishing a new collaboration with an academic partner. Should we demonstrate the therapeutic efficacy of antigen-specific BiTEs, we plan to expand our research agenda to encompass additional diseases. Furthermore, we aim to produce BiTEs for use in human biomaterial and eventually in patients.
