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Objective  Pancreatic cancer is an aggressive tumor and the prognosis remains poor. Therefore, development of more effective therapy is needed. We previously reported that  89 Zr-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  90 Y-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.  111 In-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  90 Y-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.  111 In-TSP-A01 and  111 In-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.  111 In-TSP-A01 was highly accumulated in tumors, especially in MIAPaCa-2, but this was not true of  111 In-TSP-A02. The absorbed dose for  90 Y-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  90 Y-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  90 Y-TSP-A01, but the tumor size was not reduced.    Conclusion    90 Y-TSP-A01 treatment achieved an almost complete response in MIAPaCa-2 tumors, whereas it merely inhibited the growth of BxPC-3 tumors.  90 Y-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.

plos one

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