Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, United States.
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, United States.
Nucl Med Biol. 2018 Mar;58:67-73. doi: 10.1016/j.nucmedbio.2017.12.004. Epub 2017 Dec 24.
We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted α-particle radioimmunotherapy (RIT) with Pb in ovarian cancer mouse models. In this study, we tested the binding of radiolabeled mAb 376.96 to human pancreatic ductal adenocarcinoma (PDAC) cells and localization in xenografts in immune-deficient mice and evaluated Pb-labeled 376.96 (Pb-376.96) for PDAC therapy.
In vitro Scatchard assays assessed the specific binding of Pb-376.96 to human PDAC3 adherent differentiated cells and non-adherent cancer initiating cells (CICs) dissociated from tumorspheres. In vitro clonogenic assays were used to measure the proliferation of adherent PDAC3 cells and CIC-enriched tumorspheres treated with Pb-376.96 or the irrelevant isotype-matched Pb-F3-C25. Mice bearing patient derived pancreatic cancer Panc039 xenografts were i.v. injected with 0.17-0.70 MBq Pb-376.96 or isotype control Pb-F3-C25, and used for biodistribution and tumor growth inhibition studies. Mice bearing orthotopic PDAC3 xenografts were i.v. co-injected with Tc-376.96 and I-F3-C25 and used for biodistribution studies.
Pb-376.96 specifically bound to PDAC3 adherent and dissociated tumorsphere CICs; K values averaged 9.0 and 21.7 nM, respectively, with 10-10 binding sites/cell. Pb-376.96 inhibited the clonogenic survival of PDAC3 cells or CICs dissociated from tumorspheres 3-6 times more effectively than isotype-matched control Pb-F3-C25. Panc039 s.c. tumors showed significantly higher uptake of Pb-376.96 (14.0 ± 2.1% ID/g) compared to Pb-F3-C25 (6.5 ± 0.9% ID/g, p < .001) at 24 h after dosing. Orthotopic PDAC3 tumors showed significantly higher uptake of Tc-376.96 (6.4 ± 1.8% ID/g) compared to I-F3-C25 (3.9 ± 0.9% ID/g, p < .05) at 24 h after dosing. Panc039 tumor growth was significantly inhibited by Pb-376.96 compared to Pb-F3-C25 or non-treated control tumors (p < .05).
Our results provide evidence for the efficacy of B7-H3 targeted RIT against preclinical models of pancreatic ductal adenocarcinoma (PDAC) and support future studies with Pb-376.96 in combination with chemotherapy to potentiate efficacy against PDAC.
我们最近验证了单克隆抗体（mAb）376.96 作为靶向 α 粒子放射免疫治疗（RIT）与 Pb 在卵巢癌小鼠模型中的有效载体。在这项研究中，我们测试了放射性标记的 mAb 376.96 与人胰腺导管腺癌（PDAC）细胞的结合，并评估了在免疫缺陷小鼠异种移植中的定位，并评估了 Pb 标记的 376.96（Pb-376.96）用于 PDAC 治疗。
体外 Scatchard 分析评估了 Pb-376.96 与人类 PDAC3 贴壁分化细胞和从肿瘤球中分离的非贴壁起始细胞（CICs）的特异性结合。体外集落形成试验用于测量 Pb-376.96 或无关同型匹配的 Pb-F3-C25 处理的贴壁 PDAC3 细胞和富含 CIC 的肿瘤球的增殖。携带患者来源的胰腺癌细胞 Panc039 异种移植的小鼠静脉注射 0.17-0.70 MBq Pb-376.96 或同型对照 Pb-F3-C25，并用于生物分布和肿瘤生长抑制研究。携带原位 PDAC3 异种移植的小鼠静脉注射 Tc-376.96 和 I-F3-C25，并用于生物分布研究。
Pb-376.96 特异性结合 PDAC3 贴壁和分离的肿瘤球 CIC；K 值分别平均为 9.0 和 21.7 nM，分别为 10-10 个结合位点/细胞。与同型匹配的对照 Pb-F3-C25 相比，Pb-376.96 更有效地抑制 PDAC3 细胞或从肿瘤球中分离的 CIC 的集落形成存活，抑制效果为 3-6 倍。与 Pb-F3-C25（6.5±0.9%ID/g，p<0.001）相比，24 小时后，Panc039 皮下肿瘤对 Pb-376.96 的摄取明显更高（14.0±2.1%ID/g）。与 I-F3-C25（3.9±0.9%ID/g，p<0.05）相比，24 小时后，原位 PDAC3 肿瘤对 Tc-376.96 的摄取明显更高。与 Pb-F3-C25 或未治疗的对照肿瘤相比，Pb-376.96 显著抑制 Panc039 肿瘤的生长（p<0.05）。
我们的结果为 B7-H3 靶向 RIT 针对胰腺导管腺癌（PDAC）的临床前模型的疗效提供了证据，并支持未来使用 Pb-376.96 与化疗联合的研究，以增强对 PDAC 的疗效。
