Mesothelin-targeted immunotoxin RG7787 has synergistic anti-tumor activity when combined with taxanes
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Emily Kolyvas1,4,*, Michael Rudloff1,*, Marianne Poruchynsky2, Rebekah Landsman1,5, Kevin Hollevoet1,6, David Venzon3, Christine Alewine1
1Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
3Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
4Current address: Medical College of Wisconsin, Milwaukee WI, USA
5Current address: Stritch School of Medicine, Maywood IL, USA
6Current address: Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Belgium
*These authors contributed equally to this work
Christine Alewine, email: [email protected]
Keywords: mesothelin, immunotoxin, paclitaxel, nab-paclitaxel, pancreatic cancer
Received: June 29, 2016 Accepted: December 13, 2016 Published: December 16, 2016
Recombinant immunotoxins (RITs) are antibody-based therapeutics that carry a toxin payload. The RG7787 RIT targets the cancer antigen mesothelin to deliver a recombinantly-engineered, reduced immunogenicity variant of Pseudomonas exotoxin A (PE) to the cytosol where it inhibits protein synthesis. Here we demonstrate that maximal doses of RG7787 temporarily halt growth of pancreatic cancer tumor xenografts, similar to the approved drugs gemcitabine and nab-paclitaxel, however, combination of the RIT with nab-paclitaxel produces durable complete regressions in most mice. Synergy between taxane and anti-MSLN RITs has been previously demonstrated in mouse models, but direct interaction of the combination in cell culture was not observed. Here, we show that this favorable interaction occurs in cell culture, is dependent on the dose and duration of RG7787 exposure, requires the catalytically active PE, and still occurs with RIT targeting a non-MSLN surface antigen. Unexpectedly, the combination does not increase RG7787-mediated protein synthesis inhibition nor perturb downstream apoptotic markers of RIT-mediated killing, but does augment levels of acetylated tubulin, a marker of taxane activity. Taken together, these data suggest that PE increases cell sensitivity to taxane-mediated killing by increasing taxane-mediated microtubule stability and priming cells for apoptosis by decreasing levels of the pro-survival factor Mcl-1.
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