Generation and characterisation of new potential therapeutic antibodies targeting surface PRDX4

Hörmann, Julia (2023): Generation and characterisation of new potential therapeutic antibodies targeting surface PRDX4. Dissertation, LMU München: Medizinische Fakultät

Abstract

Cancer is the second leading cause of death worldwide with an ever-growing number of people who are diagnosed with the disease. Classic therapeutic approaches are relatively unspecific, and are limited by severe adverse effects and acquired resistance to treatment, which often result in recurrent disease and death. Therefore, novel therapeutic strategies are urgently needed. Therapeutic antibodies offer a great potential as they bind their cognate antigens with high affinity and unsurpassed specificity. Some antibodies are now part of modern cancer therapeutic regimens, but an even broader application is still limited by the small number of known suitable target molecules on cancer cells. This holds true especially for solid tumours. This rises the demand to identify new targets, and for this, our group has developed an immunisation strategy based on extracellular vesicles (EVs) isolated from permanent human cancer cell lines, which turned out as an immunogenic source of known and unknown tumour associated antigens. This approach already led to the identification of interesting targets and the generation of the corresponding antibodies with clinical potential. In an attempt to identify completely new targets, we recently performed immunisations with EVs isolated from cancer patients, which can be considered as more authentic. Among others, this immunisation led to the generation of antibodies binding to peroxiredoxin 4 (PRDX4), a protein involved in the cell defense against oxidative stress and, so far, exclusively described as localised in the endoplasmic reticulum (ER) and the cytosol of cells. Much to our surprise, these antibodies detected the protein also on the surface of cancer cells, but not on normal cells. This dissertation deals with the characterisation and humanisation of PRDX4-specific antibodies, the expression profile of surface PRDX4 on normal and malignant cells and their EVs. Furthermore, it describes, for the first time, the expression of a testis-specific splice variant of PRDX4 in human cancer cells, the presence of PRDX4-specific autoantibodies in patients, as well as the identification of a new PRDX4 interaction partner, CCDC47. In summary, it provides convincing data that qualify PRDX4 as a new potential biomarker and attractive target molecule.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 10. März 2023
• 1. Bericht­erstatter:in: Zeidler, Reinhard