LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS

CC49是B72.3的第二代单抗，它与 泛癌抗原TAG-72。CC49已被证明是有效的靶向 人结肠癌异种移植，目前正在对这两种疾病进行评估 诊断和治疗临床试验。我们已经描述了 重组单链抗体的构建及鉴定 CC49。SFV被证明是一个MR 27,000同质实体， 可以有效地用125-1或131-1进行放射性标记。新陈代谢 在小鼠身上进行的研究，使用放射性标记的CC49抗体、F(ab‘)2、Fab’和SFV， 展示了极快的血浆和全身清除能力 SFV。CC49 SFV在恒河猴体内的血浆药代动力学研究 显示出非常迅速的血浆清除。ALL肿瘤靶向研究 四种放射性标记的Ig CC49形式，使用LS-174T人结肠癌 异种移植模型，显示每克肿瘤注射剂量的百分比要低得多 CC49单体SFV和Fab‘与二聚体结合的比较 F(ab‘)2和完整的免疫球蛋白。然而，肿瘤与正常组织的比例 (放射定位指数)与SFV相当或更高 而不是其他免疫球蛋白形式。因此，CC49 SFV可能在 一系列人类癌症的诊断和治疗应用。 Lu(177-Lu)是元素家族中的一员，称为 镧系元素或稀土元素。我们已经演示了第一次使用 177-Lu标记的免疫结合物177-Lu-CC49的实验治疗 人类癌症的模型。177-Lu-CC49具有延缓细胞生长的作用 在裸鼠体内一次性建立LS-1 74T人结肠癌 剂量50目次。一次给药200或350亩次 177-Lu-CC49被证明在77天内消除了已建立的肿瘤 单抗注射后观察期。剂量分级 试验表明，177-鲁-CC49(250)至少750亩词 Mu-ci/周连续3周)耐受性良好，此剂量 计划能够消除相对较大的人结肠的生长 接受治疗的动物中有90%的人移植了肿瘤。使用的优点 177-Lu标记的免疫结合物(特别是177-Lu-CC49)现在应该 被认为是人类潜在的新疗法 癌症。

CC49 is a "second generation" MAb to B72.3, which reacts with the pancarcinoma antigen TAG-72. CC49 has been shown to efficiently target human colon carcinoma xenografts and is currently being evaluated in both diagnostic and therapeutic clinical trials. We have described the construction and characterization of a recombinant single-chain Fv (sFv) of CC49. The sFv was shown to be a Mr 27,000 homogeneous entity which could be efficiently radiolabeled with 125-1 or 131-1. Metabolism studies in mice, using radiolabeled CC49 IgG, F(ab')2, Fab', and sFv, demonstrated an extremely rapid plasma and whole body clearance for the sFv. CC49 sFv plasma pharmacokinetic studies in rhesus monkeys also showed a very rapid plasma clearance. Tumor targeting studies with all four radiolabeled Ig CC49 forms, using the LS-174T human colon carcinoma xenograft model, revealed a much lower percentage injected dose/g tumor binding for the CC49 monomeric sFv and Fab' as compared to the dimeric F(ab')2 and intact IgG. However, tumor:normal tissue ratios (radiolocalization indices) for the sFv were comparable to or greater than those of the other Ig forms. The CC49 sFv may thus have utility in diagnostic and therapeutic applications for a range of human carcinomas. 177-Lutetium (177-Lu) is a member of the family of elements known as lanthanides or rare earths. We have demonstrated the first use of a 177-Lu-labeled immunoconjugate, 177-Lu-CC49, in an experimental therapy model for human carcinoma. 177-Lu-CC49 was shown to delay the growth of established LS-1 74T human colon carcinomas in athymic mice at a single dose of 50 mu-Ci. A single administration of 200 or 350 mu-Ci of 177-Lu-CC49 was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 mu-Ci of 177-Lu-CC49 (250 mu-Ci/week for 3 consecutive weeks) was well tolerated and this dose schedule was able to eliminate the growth of relatively large human colon tumor xenografts in 90% of the animals treated. The merits of the use of 177-Lu-labeled immunoconjugated (in particular, 177-Lu-CC49) should now be considered in terms of potential novel therapeutics for human carcinoma.