Barta Pavel, Laznickova Alice, Laznicek Milan, Vera Denis Rolando Beckford, Beran Milos
Department of Pharmacology and Toxicology, Charles University in Prague, Czech Republic.
J Labelled Comp Radiopharm. 2013 May 15;56(5):280-8. doi: 10.1002/jlcr.2988. Epub 2013 Jan 30.
Radiolabelled monoclonal antibodies with affinity towards tumour-associated antigens may enhance the efficacy of cancer treatment with targeted radiotherapy. The humanized antibody nimotuzumab represents a promising vector to deliver radioactivity to tumours overexpressing epidermal growth factor receptor type 1 (ErbB1). We analysed the effect of radiolabelling nimotuzumab on its uptake in cancer cells and its biodistribution profile in preclinical experiments.
Nimotuzumab was labelled with (131) I by oxidative iodination and with (177) Lu using nimotuzumab conjugates with two different chelators (DTPA and DOTA) and two different spacers (p-SCN-Bn and NHS). For the receptor studies, two cell lines (HaCaT and A431) were used. Biodistribution studies were performed in male Wistar rats.
The choice of radiolabel and the manner of its attachment to nimotuzumab had little effect on the internalization of the antibody into ErbB1-expressing cell lines. However, the type of radiolabel, the way in which it was attached to nimotuzumab and the radiolabelling procedure, significantly affected the blood clearance, liver uptake and liver persistence of radiolabelled nimotuzumab. (131) I-nimotuzumab had the longest elimination half-life and the lowest radioactivity uptake in the liver. (177) Lu-labelled nimotuzumab exhibited a shorter elimination half-life, high radioactivity and long-term retention in the liver.
对肿瘤相关抗原有亲和力的放射性标记单克隆抗体可能会增强靶向放疗的癌症治疗效果。人源化抗体尼妥珠单抗是一种很有前景的载体，可将放射性物质递送至过表达1型表皮生长因子受体（ErbB1）的肿瘤。我们在临床前实验中分析了尼妥珠单抗放射性标记对其在癌细胞中的摄取及其生物分布情况的影响。
通过氧化碘化法用（131）I标记尼妥珠单抗，并用两种不同螯合剂（二乙三胺五乙酸和四氮杂环十二烷四乙酸）和两种不同间隔物（对异硫氰酸苄酯和N-羟基琥珀酰亚胺）的尼妥珠单抗偶联物用（177）Lu标记。对于受体研究，使用了两种细胞系（HaCaT和A431）。在雄性Wistar大鼠中进行生物分布研究。
放射性标记的选择及其与尼妥珠单抗的连接方式对抗体内化到表达ErbB1的细胞系中的影响很小。然而，放射性标记的类型、其与尼妥珠单抗的连接方式以及放射性标记程序，显著影响了放射性标记尼妥珠单抗的血液清除率、肝脏摄取和肝脏滞留情况。（131）I-尼妥珠单抗的消除半衰期最长，肝脏中的放射性摄取最低。（177）Lu标记的尼妥珠单抗的消除半衰期较短，肝脏中的放射性较高且长期滞留。
