Evaluation of Efficacy of Radioimmunotherapy with 90Y-Labeled Fully Human Anti-Transferrin Receptor Monoclonal Antibody in Pancreatic Cancer Mouse Models

PLoS One. 2015 Apr 20;10(4):e0123761. doi: 10.1371/journal.pone.0123761. eCollection 2015.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Humans
  • Immunohistochemistry
  • Indium Radioisotopes
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / radiotherapy*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Radioimmunotherapy*
  • Receptors, Transferrin / immunology*
  • Tissue Distribution
  • Treatment Outcome
  • Yttrium Radioisotopes / therapeutic use*

Substances

  • Antibodies, Monoclonal
  • Indium Radioisotopes
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Receptors, Transferrin
  • Yttrium Radioisotopes

Grants and funding

This study was supported by the grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI 25861140 to AS) and the National Institute of Radiological Sciences (to TS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.