College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Albert Einstein College of Medicine, Bronx, New York.
Cancer Med. 2019 Sep;8(11):5289-5300. doi: 10.1002/cam4.2379. Epub 2019 Jul 16.
Pancreatic ductal adenocarcinoma (PDAC) accounts for >90% of pancreatic malignancies, and has median survival of <6 months. There is an urgent need for diagnostic and therapeutic options for PDAC. Centrin1 (CETN1) is a novel member of Cancer/Testis Antigens, with a 25-fold increase of CETN1 gene expression in PDX from PDAC patients. The absence of selective anti-CETN1 antibodies is hampering CETN1 use for diagnosis and therapy. Here we report the generation of highly specific for CETN1 antibodies and their evaluation for radioimmunoimaging and radioimmunotherapy (RIT) of experimental PDAC.
The antibodies to CETN1 were generated via mice immunization with immunogenic peptide distinguishing CETN1 from CETN2. Patient tumor microarrays were used to evaluate the binding of the immune serum to PDAC versus normal pancreas. The antibodies were tested for their preferential binding to CETN1 over CETN2 by ELISA. Mice bearing PDAC MiaPaCa2 xenografts were imaged with microSPECT/CT and treated with Bi- and Lu-labeled antibodies to CETN1.
Immune serum bind to 50% PDAC cases on patient tumor microarrays with no specific binding to normal pancreas. Antibodies demonstrated preferential binding to CETN1 versus CETN2. Antibody 69-11 localized to PDAC xenografts in mice in vivo and ex vivo. RIT of PDAC xenografts with Bi-labeled antibodies was effective, safe, and CETN1-specific.
The results demonstrate the ability of these novel antibodies to detect CETN1 both in vitro and in vivo; as well, the RIT treatment of experimental PDAC when radiolabeled with Bi is highly efficient and safe. Further evaluation of these novel reagents for diagnosis and treatment of PDAC is warranted.
胰腺导管腺癌（PDAC）占胰腺恶性肿瘤的>90%，中位生存期<6 个月。迫切需要 PDAC 的诊断和治疗选择。中心体蛋白 1（CETN1）是癌症/睾丸抗原的新成员，PDAC 患者的 PDX 中 CETN1 基因表达增加了 25 倍。缺乏选择性抗 CETN1 抗体阻碍了 CETN1 用于诊断和治疗。在这里，我们报告了针对 CETN1 的高度特异性抗体的产生及其在实验性 PDAC 的放射免疫成像和放射免疫治疗（RIT）中的评估。
通过用免疫原性肽免疫小鼠产生针对 CETN1 的抗体，该肽区分 CETN1 与 CETN2。患者肿瘤微阵列用于评估免疫血清与 PDAC 与正常胰腺的结合。通过 ELISA 测试抗体对 CETN1 的优先结合与 CETN2 的结合。用微 SPECT/CT 对携带 PDAC MiaPaCa2 异种移植物的小鼠进行成像，并使用 Bi-和 Lu-标记的 CETN1 抗体进行治疗。
免疫血清与 50%的 PDAC 病例在患者肿瘤微阵列上结合，与正常胰腺无特异性结合。抗体显示出对 CETN1 与 CETN2 的优先结合。抗体 69-11 在体内和体外定位于小鼠的 PDAC 异种移植物。用 Bi 标记的抗体进行 PDAC 异种移植物的 RIT 是有效、安全和 CETN1 特异性的。
这些结果表明这些新型抗体具有在体外和体内检测 CETN1 的能力；此外，用 Bi 放射性标记进行实验性 PDAC 的 RIT 治疗非常有效且安全。需要进一步评估这些新型试剂用于 PDAC 的诊断和治疗。
