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, rITs are internalized, traverses various intracellular compartments, and ADP-ribosylates EF2 in the cytosol. The covalent modification arrests protein synthesis driving the targeted cells towards apoptosis (Figure 2).
Our research group uses syngeneic animal models to study effects of rIT-induced cell death on the host immune system. Goal of our research is to understand the molecular and cellular mechanism behind the specific anti-cancer immune activation in syngeneic animal model systems and to combine rIT with immune modulatory drugs.
In addition, our group develops novel targets for conventional rITs, develops patented, novel toxins, and integrates rITs in established drug combinations to further improve outcome of cancer (immune-) therapies.
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.