LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS

鼠IgG1单抗B72.3已被证明能与一种高分子的 重量糖蛋白(指定为Tag-72)在许多上皮源性细胞中发现 癌症，对正常成人组织的反应性最低。B72.3是， 因此，被选为抗体可能被用于 人类肿瘤和IS的放射免疫检测和放射免疫治疗 在LS-174T人结肠癌模型系统中进行评估 以确定异种移植的可行性这些研究的一些新的 已经开发了螯合物结合物，使其能够结合 从放射性金属到蛋白质。这些新的构造物已经共价 与B72.3免疫球蛋白相关联，以确定哪个结果最好 In-Ill和Y-88标记后的生物分布 对于Y-90)。进行了剂量分级研究，并证明了 分割放射性标记单抗的治疗剂量可以减少 毒性和提高疗效。B72.3的重组/嵌合形式 是利用小鼠B72.3和人类的可变区 重链和轻链恒定区。 已经开发出新的抗TAG-72单抗(指定为CC)，并与 B72.3在LS-174T模型系统中。所有产品都显示出较高的ID/gm百分比 肿瘤：组织比B72.3；药代动力学差异为 在CC单抗中注明。 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，相对较小(27kD)的单链分子 可以有效地靶向人类肿瘤异种移植瘤。

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.