title: Mesothelin-targeted immunotoxin RG7787 has synergistic anti-tumor activity when combined with taxanes.
abstract: 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.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Current address: Medical College of Wisconsin, Milwaukee WI, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Kolyvas
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rudloff
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Poruchynsky
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Current address: Stritch School of Medicine, Maywood IL, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Landsman
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Current address: Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Belgium.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hollevoet
authors.affiliation: Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Venzon
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Alewine
mesh_terms: D000107:Acetylation; D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D000090204:Mesothelin; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000074322:Antineoplastic Agents, Immunological; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; C000715527:MSLN protein, human; C579094:Mcl1 protein, mouse; C000715528:Msln protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D014404:Tubulin; D050257:Tubulin Modulators; C000597116:LMB-100; D000090204:Mesothelin; D017239:Paclitaxel
keywords: immunotoxin; mesothelin; nab-paclitaxel; paclitaxel; pancreatic cancer