LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS

MAb B72.3是一种鼠IgG 1，已显示与高分子量 重量糖蛋白（命名为TAG-72），发现在许多上皮来源的 癌症，对正常成人组织具有最小的反应性。 B72.3是， 因此，选择作为可能用于 放射免疫检测和放射免疫治疗， 在使用LS-174 T人结肠癌的模型系统中进行评价 异种移植，以确定这些研究的可行性。 已经开发了螯合物-缀合物， 放射性金属到蛋白质。 这些新的结构已经被共价地 与B72.3 IgG连接，以确定哪种方法最佳 用In-III和Y-88（用作替代物）标记后的生物分布 Y-90）。 进行了剂量分次研究，并证明 将放射性标记的单克隆抗体的剂量分开用于治疗可以减少 毒性和增加功效。 B72.3的重组/嵌合形式具有 使用鼠B72.3和人B72.3的可变区， 重链和轻链恒定区。 已经开发了新的抗TAG-72单克隆抗体（命名为CC），并与 B72.3在LS-174 T模型系统中。 所有均表现出较高的%ID/gm， 肿瘤：组织比B72.3;药代动力学差异为 在CC MAB中注意到。 肿瘤靶向和药代动力学研究也使用 基因工程单链抗原结合蛋白（sFv）。 这些 研究表明，一个相对较小的（27 kD）单链分子， 可以有效地靶向人肿瘤异种移植物。

MAb B72.3, a murine IgG1, has been shown to react with a high molecular weight glycoprotein (designated TAG-72) found in many epithelial-derived cancers, with minimal reactivity to normal adult tissues. B72.3 was, therefore, chosen as an antibody that could potentially be used for radioimmunodetection and radioimmunotherapy of human carcinomas and is being evaluated in model systems using the LS-174T human colon carcinoma xenograft to determine the feasibility of these studies A number of new chelate-conjugates have been developed enabling the binding of radiometals to proteins. These new constructs have been covalently linked to B72.3 IgG to determine which resulted in the best biodistribution after labeling with In-Ill and Y-88 (used as a substitute for Y-90). Dose fractionation studies were carried out and demonstrated that splitting the dose of a radiolabeled MAb for therapy can reduce toxicity and increase efficacy. A recombinant/chimeric form of B72.3 has been developed using the variable regions of the murine B72.3 and human heavy chain and light chain constant regions. New anti-TAG-72 MAbs (designated CC) have been developed and compared to B72.3 in the LS-174T model system. All exhibited higher %ID/gm and tumor:tissue ratios than B72.3; differences in the pharmacokinetics were noted among the CC MAbs. Tumor targeting and pharmacokinetic studies were also carried out using a genetically engineered single chain antigen binding protein (sFv). These studies demonstrated that a relatively small (27kD) single chain molecule can efficiently target a human tumor xenograft.