Radioimmunotherapy of pancreatic cancer xenografts in nude mice using 90Y-labeled anti-α6β4 integrin antibody

// Winn Aung 1 , Atsushi B. Tsuji 1 , Hitomi Sudo 1 , Aya Sugyo 1 , Yoshinori Ukai 2 , Katsushi Kouda 2 , Yoshikazu Kurosawa 3 , Takako Furukawa 1 , Tsuneo Saga 1 1 Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan 2 Perseus Proteomics Inc., Tokyo, Japan 3 Innovation Center for Advanced Medicine, Fujita Health University, Toyoake, Japan Correspondence to: Winn Aung, email: winn@nirs.go.jp Keywords: targeted radioimmunotherapy, pancreatic tumor, α 6 β 4 integrin, yttrium-90, radiolabeled antibody Received: December 10, 2015      Accepted: May 04, 2016      Published: May 26, 2016 ABSTRACT The contribution of integrin α 6 β 4 (α 6 β 4 ) overexpression to the pancreatic cancer invasion and metastasis has been previously shown. We have reported immunotargeting of α 6 β 4 for radionuclide-based and near-infrared fluorescence imaging in a pancreatic cancer model. In this study, we prepared yttrium-90 labeled anti-α 6 β 4 antibody ( 90 Y-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 90 Y-ITGA6B4 (3.7MBq), (2) double administrations of 90 Y-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 90 Y-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 90 Y-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 90 Y-ITGA6B4 is a promising radioimmunotherapeutic agent against α 6 β 4 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.