Nakamura K, Kubo A
Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
Cancer. 1997 Dec 15;80(12 Suppl):2650-5. doi: 10.1002/(sici)1097-0142(19971215)80:12+<2650::aid-cncr41>3.0.co;2-8.
Some vasoactive drugs have been studied in the hope of altering the vascular permeability and/or blood of tumors to enhance monoclonal antibody (MoAb) uptake. The pretreatment of interleukin-2 (IL-2), one of the vasoactive reagents, produced a generalized vascular permeability, but its function was not tumor specific. Conversely, MoAb/IL-2 immunoconjugates were developed that selectively alter the vasopermeability of tumors. In the current study the authors evaluated whether radiolabeled anti-carcinoembryonic antigen (CEA) MoAb, ZCE025/IL-2 immunoconjugate, specifically can enhance delivery of iodine-125 (I-125) to tumor sites.
ZCE025 was conjugated with IL-2, and the conjugate then labeled with I-125. Biodistribution studies were performed in athymic mice bearing CEA-producing human tumor (MKN45) xenografts. Mice were injected with I-125-ZCE025/IL-2 conjugate, and I-125 activities in the organs, including blood and tumor, were investigated at 1, 3, and 5 days after injection. Vascular permeability of the organs, including tumors, also was studied by using I-131 labeled mouse serum albumin in three groups.
I-125 labeled ZCE025/IL-2 conjugate destroyed its lymphokine-activated killer cell (LAK) activation, but retained a minimum of 75% of the antibody binding reactivity. Biodistribution of I-125-ZCE025/IL-2 conjugate showed increased uptake of I-125 in tumor by a factor of 1.5, 4.2, and 4.1 compared with I-125-ZCE025 on Days 1, 3, and 5, respectively. In contrast, I-125 distribution was not enhanced in any organs except the tumor. Vascular permeability studies demonstrated that the physiologic effect of IL-2 was tumor specific in the mice that received the I-125-ZCE025/IL-2 conjugate.
These studies indicate that the administration of radiolabeled MoAb/IL-2 double conjugate may enhance the therapeutic potential of radiolabeled MoAb without any pretreatment with IL-2 or repeated injection of MoAb.
一些血管活性药物已被研究，以期改变肿瘤的血管通透性和/或血流，从而增强单克隆抗体（MoAb）的摄取。血管活性试剂之一白细胞介素-2（IL-2）预处理可产生全身性血管通透性，但它的作用并非肿瘤特异性的。相反，已研发出MoAb/IL-2免疫缀合物，其可选择性改变肿瘤的血管通透性。在本研究中，作者评估了放射性标记的抗癌胚抗原（CEA）单克隆抗体ZCE025/IL-2免疫缀合物是否能特异性增强碘-125（I-125）向肿瘤部位的递送。
将ZCE025与IL-2偶联，然后用I-125标记该偶联物。在携带产生CEA的人肿瘤（MKN45）异种移植瘤的无胸腺小鼠中进行生物分布研究。给小鼠注射I-125-ZCE025/IL-2偶联物，并在注射后1、3和5天研究包括血液和肿瘤在内的各器官中的I-125活性。还通过在三组中使用I-131标记的小鼠血清白蛋白研究了包括肿瘤在内的各器官的血管通透性。
I-125标记的ZCE025/IL-2偶联物破坏了其淋巴因子激活的杀伤细胞（LAK）活性，但保留了至少75%的抗体结合反应性。I-125-ZCE025/IL-2偶联物的生物分布显示，与I-125-ZCE025相比，在第1、3和5天肿瘤对I-125的摄取分别增加了至1.5倍、4.2倍和4.1倍。相比之下，除肿瘤外，I-125在任何器官中的分布均未增强。血管通透性研究表明，IL-2的生理作用在接受I-125-ZCE025/IL-2偶联物的小鼠中具有肿瘤特异性。
这些研究表明，给予放射性标记的MoAb/IL-2双偶联物可能增强放射性标记的MoAb的治疗潜力，而无需用IL-2进行任何预处理或重复注射MoAb。
