Photo: Franziska Gsottberger, Dr. Fabian Müller, Charlotte Emmerich. (Anna Ammon, Christina Meier).
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.
Müller F, Cunningham T, Stookey S, Tai CH, Burkett S, Jailwala P, Stetler Stevenson M, Cam MC, Wayne AS, Pastan I. 5-Azacytidine prevents relapse and produces long-term complete remissions in leukemia xenografts treated with Moxetumomab pasudotox. Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1867-E1875. doi: 10.1073/pnas.1714512115. Epub 2018 Feb 5. PubMed PMID: 29432154.
Müller F, Stookey S, Cunningham T, Pastan I. Paclitaxel synergizes with exposure time adjusted CD22-targeting immunotoxins against B-cell malignancies. Oncotarget. 2017 May 9;8(19):30644-30655. doi: 10.18632/oncotarget.16141. PubMed PMID: 28423727; PubMed Central PMCID: PMC5458156.
Müller F, Cunningham T, Liu XF, Wayne AS, 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. 2016 Oct 1;22(19):4913-4922. Epub 2016 Apr 25. PubMed PMID: 27114443; PubMed Central PMCID: PMC5050065.
Liu X, Müller F, Wayne AS, Pastan I. Protein Kinase Inhibitor H89 Enhances the Activity of Pseudomonas Exotoxin A-Based Immunotoxins. Mol Cancer Ther. 2016 May;15(5):1053-62. doi: 10.1158/1535-7163.MCT-15-0828. Epub 2016 Mar 3. PubMed PMID: 26939705; PubMed Central PMCID: PMC4873377.
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. PLoS One. 2015 Mar 24;10(3):e0122462. doi: 10.1371/journal.pone.0122462. eCollection 2015. PubMed PMID: 25803818; PubMed Central PMCID: PMC4372481.