LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS

使用标记的单克隆抗体进行定位和治疗——模型系统

• 批准号: 3796502
• 负责人: J SCHLOM
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3796502
• 关键词: Macaca mulatta; antitumor antibody; athymic mouse; carcinoma; clearance rate; colon neoplasms; genetic manipulation; immunoconjugates; immunoglobulin structure; monoclonal antibody; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; pharmacokinetics; radiation therapy dosage; radionuclides; rare earth element; tumor antigens

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.

CC 49是针对B72.3的“第二代”单克隆抗体，其与B72.3反应。 泛癌抗原TAG-72。 CC 49已被证明有效靶向 人结肠癌异种移植物，目前正在评估这两个 诊断和治疗临床试验。 我们已经描述了 重组单链抗体（sFv）的构建和表征 CC 49的 sFv显示为Mr 27，000的同质实体， 可以有效地用125-1或131-1进行放射性标记。 代谢 使用放射性标记的CC 49 IgG、F（ab '）2、Fab'和sFv在小鼠中进行的研究， 证明了对这些药物的血浆和全身清除速度极快， sFv。 在恒河猴中的CC 49 sFv血浆药代动力学研究也 显示出非常快的血浆清除率。 所有肿瘤靶向研究 四种放射性标记的IG CC 49形式，使用LS-174 T人结肠癌 异种移植模型，显示出低得多的百分比注射剂量/g肿瘤 CC 49单体sFv和Fab'与二聚体sFv和Fab'的结合 F（ab '）2和完整IgG。 然而，肿瘤：正常组织比 sFv的放射性定位指数（放射性定位指数）与 而不是其他IG形式。 因此，CC 49 sFv可以在免疫治疗中具有实用性。 用于一系列人类癌症的诊断和治疗应用。 177-镥（177-Lu）是元素家族中的一员， 镧系元素或稀土元素。 我们已经展示了第一次使用 177-Lu标记的免疫缀合物，177-Lu-CC 49，在实验性治疗中 人癌模型。177-Lu-CC 49显示出延迟 在无胸腺小鼠中建立的LS-1 74 T人结肠癌， 剂量为50 μ Ci。 单次给予200或350 μ Ci的 177-Lu-CC 49显示在77天内消除已建立的肿瘤。 MAb给药后的观察期。 剂量分割 实验表明，至少750 μ Ci的177-Lu-CC 49（250 μ Ci/周，连续3周）的耐受性良好， 时间表能够消除相对较大的人类结肠的生长 90%接受治疗的动物出现肿瘤异种移植。 使用的优点 177-Lu标记的免疫缀合物（特别是177-Lu-CC 49）现在应 被认为是潜在的新的治疗方法， carcinoma.