Franziska Wagner, Dr. Fabian Müller, Charlotte Wagner
Recombinant immunotoxins (rIT) are fusion proteins of an antibody and Pseudomonas exotoxin A (PE, Figure 1). The antibody directs the rIT selectively towards tumor cells while healthy tissue remains unaffected. After binding, the rIT is internalized, traverses various intracellular compartments, and ADP-ribosylates EF2 in the cytosol; protein synthesis is arrested and cells activate their cell death program (Figure 2).
Our young research group focuses on the immune activating effects induced when specifically killing cancer cells with rIT. Goal of our research is to understand the molecular and cellular mechanism behind the specific anti-cancer immune activation in syngeneic animal model systems.
In addition to working with existing rIT developed by Dr. Ira Pastan, LMB, NCI, NIH, USA, our group works on new targets for conventional rITs and on novel toxin concepts to further improve their efficacy against cancer.
Mueller, F., Cunningham, T., Liu, X., Wayne, A. S. & Pastan, I. Wide variability in the time required for immunotoxins to kill B lineage acute lymphoblastic leukemia cells: Implications for trial design. Clin. Cancer Res., doi:10.1158/1078-0432.CCR-15-2500 (2016).
Liu, X.*, Mueller, F.*, Wayne, A. S. & Pastan, I. Protein kinase inhibitor H89 enhances the activity of Pseudomonas exotoxin A-based immunotoxins. Mol. Cancer Ther., doi:10.1158/1535-7163.MCT-15-0828 (2016).
Hollevoet K, Mason-Osann E, Müller F, Pastan I. Methylation-associated partial down-regulation of mesothelin causes resistance to anti-mesothelin immunotoxins in a pancreatic cancer cell line. PLosONE. Mar 24;10(3):e0122462. doi: 10.1371/journal.pone.0122462 (2014).