title: Evaluation of Efficacy of Radioimmunotherapy with 90Y-Labeled Fully Human Anti-Transferrin Receptor Monoclonal Antibody in Pancreatic Cancer Mouse Models.
abstract: OBJECTIVE
  Pancreatic cancer is an aggressive tumor and the prognosis remains poor. Therefore, development of more effective therapy is needed. We previously reported that 89Zr-labeled TSP-A01, an antibody against transferrin receptor (TfR), is highly accumulated in a pancreatic cancer xenograft, but not in major normal organs. In the present study, we evaluated the efficacy of radioimmunotherapy (RIT) with 90Y-TSP-A01 in pancreatic cancer mouse models.
  
  
  METHODS
  TfR expression in pancreatic cancer cell lines (AsPC-1, BxPC-3, MIAPaCa-2) was evaluated by immunofluorescence staining. 111In-labeled anti-TfR antibodies (TSP-A01, TSP-A02) were evaluated in vitro by cell binding assay with the three cell lines and by competitive inhibition assay with MIAPaCa-2. In vivo biodistribution was evaluated in mice bearing BxPC-3 and MIAPaCa-2 xenografts. Tumor volumes of BxPC-3 and MIAPaCa-2 were sequentially measured after 90Y-TSP-A01 injection and histological analysis of tumors was conducted.
  
  
  RESULTS
  MIAPaCa-2 cells showed the highest TfR expression, followed by AsPC-1 and BxPC-3 cells. 111In-TSP-A01 and 111In-TSP-A02 bound specifically to the three cell lines according to TfR expression. The dissociation constants for TSP-A01, DOTA-TSP-A01, TSP-A02, and DOTA-TSP-A02 were 0.22, 0.28, 0.17, and 0.22 nM, respectively. 111In-TSP-A01 was highly accumulated in tumors, especially in MIAPaCa-2, but this was not true of 111In-TSP-A02. The absorbed dose for 90Y-TSP-A01 was estimated to be 8.3 Gy/MBq to BxPC-3 and 12.4 Gy/MBq to MIAPaCa-2. MIAPaCa-2 tumors treated with 3.7 MBq of 90Y-TSP-A01 had almost completely disappeared around 3 weeks after injection and regrowth was not observed. Growth of BxPC-3 tumors was inhibited by 3.7 MBq of 90Y-TSP-A01, but the tumor size was not reduced.
  
  
  CONCLUSIONS
  90Y-TSP-A01 treatment achieved an almost complete response in MIAPaCa-2 tumors, whereas it merely inhibited the growth of BxPC-3 tumors. 90Y-TSP-A01 is a promising RIT agent for pancreatic cancer, although further investigation is necessary to improve the efficacy for the radioresistant types like BxPC-3.
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sugyo
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, 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, Inage-ku, Chiba, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sudo
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Nuclear Medicine, Cancer Institute Hospital, Koto-ku, Tokyo, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Koizumi
authors.affiliation: Reserch and Development Division, Perseus Proteomics Inc., Meguro-ku, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Satoh
authors.affiliation: Innovation Center for Advanced Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Gene
authors.initials: G
authors.lastname: Kurosawa
authors.affiliation: Innovation Center for Advanced Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kurosawa
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D007205:Indium Radioisotopes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D016499:Radioimmunotherapy; D011990:Receptors, Transferrin / Q000276:immunology*; D014018:Tissue Distribution; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011990:Receptors, Transferrin; D015021:Yttrium Radioisotopes