title: Radioimmunotherapy of pancreatic cancer xenografts in nude mice using 90Y-labeled anti-α6β4 integrin antibody.
abstract: The contribution of integrin α6β4 (α6β4) overexpression to the pancreatic cancer invasion and metastasis has been previously shown. We have reported immunotargeting of α6β4 for radionuclide-based and near-infrared fluorescence imaging in a pancreatic cancer model. In this study, we prepared yttrium-90 labeled anti-α6β4 antibody (90Y-ITGA6B4) and evaluated its radioimmunotherapeutic efficacy against pancreatic cancer xenografts in nude mice. Mice bearing xenograft tumors were randomly divided into 5 groups: (1) single administration of 90Y-ITGA6B4 (3.7MBq), (2) double administrations of 90Y-ITGA6B4 with once-weekly schedule (3.7MBq x 2), (3) single administration of unlabeled ITGA6B4, (4) double administrations of unlabeled ITGA6B4 with once-weekly schedule and (5) the untreated control. Biweekly tumor volume measurements and immunohistochemical analyses of tumors at 2 days post-administration were performed to monitor the response to treatments. To assess the toxicity, body weight was measured biweekly. Additionally, at 27 days post-administration, blood samples were collected through cardiac puncture, and hematological parameters, hepatic and renal functions were analyzed. Both 90Y-ITGA6B4 treatment groups showed reduction in tumor volumes (P < 0.04), decreased cell proliferation marker Ki-67-positive cells and increased DNA damage marker p-H2AX-positive cells, compared with the other groups. Mice treated with double administrations of 90Y-ITGA6B4, exhibited myelosuppression. There were no significant differences in hepatic and renal functions between the 2 treatment groups and the other groups. Our results suggest that 90Y-ITGA6B4 is a promising radioimmunotherapeutic agent against α6β4 overexpressing tumors. In the future studies, dose adjustment for fractionated RIT should be considered carefully in order to get the optimal effect while avoiding myelotoxicity.
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Winn
authors.initials: W
authors.lastname: Aung
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sudo
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sugyo
authors.affiliation: Perseus Proteomics Inc., Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ukai
authors.affiliation: Perseus Proteomics Inc., Tokyo, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kouda
authors.affiliation: Innovation Center for Advanced Medicine, Fujita Health University, Toyoake, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kurosawa
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight; D045744:Cell Line, Tumor; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry; D006801:Humans; D039161:Integrin alpha6beta4 / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000532:radiotherapy*; D049268:Positron-Emission Tomography; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000737:chemistry*
chemical_list: D000911:Antibodies, Monoclonal; D039161:Integrin alpha6beta4; D015021:Yttrium Radioisotopes; D019788:Fluorodeoxyglucose F18; C000615496:Yttrium-90
keywords: pancreatic tumor; radiolabeled antibody; targeted radioimmunotherapy; yttrium-90; α6β4 integrin