Hnatowich D J, Rusckowski M, Brill A B, Siebecker D A, Misra H, Mardirossian G, Bushe H, Rescigno A, Stevens S, Johnson D K
University of Massachusetts Medical Center, Worcester 01655.
Cancer Res. 1990 Nov 15;50(22):7272-8.
The pharmacokinetics of the C110 anti-carcinoembryonic antigen antibody radiolabeled with 111In via a novel benzylisothiocyanate derivative of diethylenetriamine pentaacetic acid have been determined in 12 patients. The chelator was attached to the protein via a thiourea bond and in such a way that all 5 carboxymethyl arms were presumably able to participate in chelation. Patients with known or suspected colorectal carcinoma received between 5 and 20 mg of the IgG antibody labeled with 5 mCi of 111In. Individual organ radioactivity levels were quantitated, and serum and urine samples were analyzed, principally by size exclusion high-performance liquid chromatography (HPLC). Total urinary excretion averaged 0.18% of the injected dose/h with large patient to patient variation. At early times postadministration (less than 8 h) the predominant radiolabeled species in urine was free diethylenetriamine pentaacetic acid most probably administered as a small radiocontaminant in the injectate. Thereafter, radioactivity in urine was primarily present as a low molecular weight catabolic product. Analysis of serum by size exclusion HPLC occasionally showed 3 radioactivity peaks, 2 of which are due to circulating immune complexes and labeled antibody. The third peak is of low molecular weight and is due to one or more products of antibody catabolism. Transchelation of 111In to circulating transferrin was observed but at modest levels. Quantitation of organ radioactivity showed that 18 +/- 4 (SD)% of the injected dose was in the liver at 1 day postadministration and 1.4 +/- 1.1 and 1.2 +/- 0.9% was in the spleen and in both kidneys, respectively, at this time. The mean half-life for clearance of total injected radioactivity was fitted to a single exponential and was found to be 34 h (SD, 14 h; N = 13) and that for antibody alone, assessed by size exclusion HPLC analysis of serum samples, was calculated to be 22 h (SD, 8 h; N = 10). Neither of these values nor organ radioactivity levels were affected by antibody-loading dose.
通过二乙烯三胺五乙酸的新型苄基异硫氰酸酯衍生物用¹¹¹In 标记的 C110 抗癌胚抗原抗体的药代动力学已在 12 名患者中确定。螯合剂通过硫脲键连接到蛋白质上，使得所有 5 个羧甲基臂大概都能够参与螯合。已知或疑似患有结直肠癌的患者接受了 5 至 20 mg 用 5 mCi 的¹¹¹In 标记的 IgG 抗体。对各个器官的放射性水平进行了定量，并对血清和尿液样本进行了分析，主要采用尺寸排阻高效液相色谱法（HPLC）。总尿排泄量平均为注射剂量的 0.18%/小时，患者之间差异很大。给药后早期（少于 8 小时），尿液中主要的放射性标记物是游离的二乙烯三胺五乙酸，很可能是作为注射剂中的少量放射性污染物给药的。此后，尿液中的放射性主要以低分子量分解代谢产物的形式存在。通过尺寸排阻 HPLC 分析血清偶尔会显示 3 个放射性峰，其中 2 个是由于循环免疫复合物和标记抗体。第三个峰分子量较低，是由于抗体分解代谢的一种或多种产物。观察到¹¹¹In 向循环转铁蛋白的转螯合，但水平适中。器官放射性定量显示，给药后 1 天，注射剂量的 18±4（标准差）%在肝脏中，此时脾脏和双肾中的放射性分别为 1.4±1.1%和 1.2±0.9%。总注射放射性清除的平均半衰期拟合为单指数，发现为 34 小时（标准差，14 小时；N = 13），通过血清样本的尺寸排阻 HPLC 分析评估的仅抗体的半衰期计算为 22 小时（标准差，8 小时；N = 10）。这些值和器官放射性水平均不受抗体负载剂量的影响。
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