title: Preclinical evaluation of ⁸⁹Zr-labeled human antitransferrin receptor monoclonal antibody as a PET probe using a pancreatic cancer mouse model.
abstract: OBJECTIVE
  Pancreatic cancer is aggressive and its prognosis remains poor; thus, effective therapy is urgently needed. Transferrin receptor (TfR) is highly expressed in pancreatic cancer and is considered to be a good candidate for molecular-targeted therapy. We radiolabeled and evaluated fully human anti-TfR monoclonal antibodies as a new PET probe for evaluating the biodistribution of the anti-TfR antibody in pancreatic cancer.
  
  
  METHODS
  TfR expression was evaluated in four human pancreatic cancer (MIAPaCa-2, PANC-1, BxPC-3, and AsPC-1) and murine A4 cell lines. The binding of 125I-labeled anti-TfR antibodies (TSP-A01, TSP-A02, TSP-A03, and TSP-A04) to MIAPaCa-2 cells was compared. 125I-labeled, 67Ga-labeled, and 89Zr-labeled TSP-A01 were evaluated by cell binding, competitive inhibition, and internalization assays. Biodistribution studies of 125I-labeled and 89Zr-labeled TSP-A01 were conducted in mice bearing MIAPaCa-2 and A4 tumors. PET imaging with [89Zr]TSP-A01 was carried out.
  
  
  RESULTS
  MIAPaCa-2 cells showed the highest TfR expression in vitro and in vivo, whereas A4 cells showed no expression. Of the four antibodies, [125I]TSP-A01 showed the highest binding to MIAPaCa-2 cells, but not to A4 cells. The dissociation constant of TSP-A01 was 0.29 nmol/l. Uptake of radiolabeled TSP-A01, especially [89Zr]TSP-A01, was significantly higher in MIAPaCa-2 tumors than in A4 tumors. PET with [89Zr]TSP-A01 clearly visualized MIAPaCa-2 xenografts but not A4 xenografts.
  
  
  CONCLUSIONS
  [89Zr]TSP-A01 is a promising PET probe for evaluating the accumulation of anti-TfR antibody in pancreatic cancer and has the potential to facilitate the selection of appropriate patients who would benefit from anti-TfR antibody therapy.
authors.affiliation: aDiagnostic Imaging Program bMolecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba cDepartment of Nuclear Medicine, Cancer Institute Hospital dResearch and Development Division, Perseus Proteomics Inc., Tokyo eInnovation Center for Advanced Medicine, School of Medicine, Fujita Health University, Aichi, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sugyo
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sudo
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nagatsu
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Koizumi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ukai
authors.forename: Gene
authors.initials: G
authors.lastname: Kurosawa
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kurosawa
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes; D011990:Receptors, Transferrin / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution; D015040:Zirconium
chemical_list: D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D011990:Receptors, Transferrin; D015040:Zirconium