title: In vitro and in vivo activity of the low-immunogenic antimesothelin immunotoxin RG7787 in pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. RG7787 is a novel low-immunogenic antimesothelin recombinant immunotoxin (RIT), engineered to overcome the limitations of SS1P, a RIT now in clinical trials. In vitro activity was evaluated on five established PDAC cell lines (KLM-1, AsPC-1, BxPC-3, Panc 3.014, and PK-1) and on PDAC cells directly established from a patient tumor (GUMC108). RG7787 had subnanomolar IC50s in most cell lines, and was significantly more active than SS1P in GUMC108, KLM-1, and Panc 3.014 cells. GUMC108 was most sensitive, with RG7787 killing >99% of the cells. In a subcutaneous KLM-1 xenograft mouse model, two cycles of 3 × 2.5 mg/kg RG7787 QOD combined with two cycles of 1 × 50 mg/kg paclitaxel induced near-complete responses, with all tumors regressing below 5 mm(3) within 30 days after therapy was initiated (>95% decrease) and no significant growth increase for at least another 3 weeks. RG7787 alone gave limited but significant regressions and paclitaxel by itself arrested tumor growth. Quantifying the uptake of Alexa Fluor 647-labeled RG7787 in tumors showed that the RIT reached only 45% of KLM-1 cells, accounting in part for the limited responses. Paclitaxel did not improve RG7787 uptake, which thus cannot explain the beneficial effect of the combination therapy. In conclusion, RG7787 has high cytotoxic activity on PDAC cell lines as well as on primary patient cells. In vivo, this novel RIT gives durable near-complete tumor responses when combined with paclitaxel. RG7787 merits further evaluation for the treatment of PDAC.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland; Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hollevoet
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland;
authors.forename: Emily
authors.initials: E
authors.lastname: Mason-Osann
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland;
authors.forename: Xiu-fen
authors.initials: XF
authors.lastname: Liu
authors.affiliation: Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Penzberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Imhof-Jung
authors.affiliation: Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Penzberg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Niederfellner
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland; pastani@mail.nih.gov.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000090204:Mesothelin; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; D011500:Protein Synthesis Inhibitors; C474515:SS1(dsFv)PE38; C000597116:LMB-100; D000090204:Mesothelin