Sugyo Aya, Tsuji Atsushi B, Sudo Hitomi, Okada Maki, Koizumi Mitsuru, Satoh Hirokazu, Kurosawa Gene, Kurosawa Yoshikazu, Saga Tsuneo
Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
PLoS One. 2015 Apr 20;10(4):e0123761. doi: 10.1371/journal.pone.0123761. eCollection 2015.
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.
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.
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.
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.
胰腺癌是一种侵袭性肿瘤，预后仍然很差。因此，需要开发更有效的治疗方法。我们之前报道过，89Zr标记的TSP-A01，一种抗转铁蛋白受体（TfR）抗体，在胰腺癌异种移植瘤中高度聚集，但在主要正常器官中没有。在本研究中，我们评估了90Y-TSP-A01在胰腺癌小鼠模型中的放射免疫治疗（RIT）疗效。
通过免疫荧光染色评估胰腺癌细胞系（AsPC-1、BxPC-3、MIAPaCa-2）中TfR的表达。通过与三种细胞系的细胞结合试验以及与MIAPaCa-2的竞争抑制试验，在体外评估111In标记的抗TfR抗体（TSP-A01、TSP-A02）。在携带BxPC-3和MIAPaCa-2异种移植瘤的小鼠中评估体内生物分布。注射90Y-TSP-A01后，依次测量BxPC-3和MIAPaCa-2的肿瘤体积，并对肿瘤进行组织学分析。
MIAPaCa-2细胞显示出最高的TfR表达，其次是AsPC-1和BxPC-3细胞。111In-TSP-A01和111In-TSP-A02根据TfR表达特异性结合到三种细胞系。TSP-A01、DOTA-TSP-A01、TSP-A02和DOTA-TSP-A02的解离常数分别为0.22、0.28、0.17和0.22 nM。111In-TSP-A01在肿瘤中高度聚集，尤其是在MIAPaCa-2中，但111In-TSP-A02并非如此。估计90Y-TSP-A01对BxPC-3的吸收剂量为8.3 Gy/MBq，对MIAPaCa-2为12.4 Gy/MBq。用3.7 MBq的90Y-TSP-A01治疗的MIAPaCa-2肿瘤在注射后约3周几乎完全消失，未观察到再生长。3.7 MBq的90Y-TSP-A01抑制了BxPC-3肿瘤的生长，但肿瘤大小未减小。
90Y-TSP-A01治疗在MIAPaCa-2肿瘤中实现了几乎完全缓解，而对BxPC-3肿瘤仅抑制了生长。90Y-TSP-A0
