THE EFFECT OF ANTIBODY PROTEIN DOSE ON THE UNIFORMITY OF TUMOR DISTRIBUTION OF RADIOANTIBODIES - AN AUTORADIOGRAPHIC STUDY
THE EFFECT OF ANTIBODY PROTEIN DOSE ON THE UNIFORMITY OF TUMOR DISTRIBUTION OF RADIOANTIBODIES - AN AUTORADIOGRAPHIC STUDY
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DOI：
10.1007/bf01741594
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发表时间：
1991-08-01
影响因子：
5.8
通讯作者：
GOLDENBERG, DM
中科院分区：
文献类型：
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作者：
BLUMENTHAL, RD;FAND, I;GOLDENBERG, DM
放射性标记的抗体难以到达实体瘤的血管化不良区域，可能会降低这些大分子的治疗效果。 理论数学模型预测，增加蛋白质给药剂量将降低放射性抗体分布的异质性。 进行这项研究是为了在实验动物模型中评估这一假设。 我们利用宏观放射自显影技术证实低亲和力I-125标记的NP-4或高亲和力Immu-14抗癌胚抗原的肿瘤穿透增加（抗CEA）mAb（60.25-0.4 g）和大号（0.8- 1.5g）GW-39和LS 174 T人结肠异种移植物，在裸鼠中皮下生长，当400 μ g未标记抗体与10 μ g（100 μ Ci）放射性抗体同时给药时。 蛋白质进一步增加至800 μ g会导致肿瘤对抗体的总摄入减少。 mAb分布的这些差异早在抗体注射后1天就可以观察到。 使用800 μ g未标记的抗体，Mu-9抗CSAp（抗粘蛋白）抗体也实现了改进的mAb渗透。 注射后3天发现不相关抗体（AFP-7-31）均匀分布，即使在低蛋白剂量下也是如此。 通过增加GS-2结直肠肿瘤中的蛋白剂量来改善mAb渗透的尝试没有成功，GS-2结直肠肿瘤是一种具有低NP-4增长的模型，其结果是将抗体与抗原分离的生理屏障。 这些结果表明，通过仔细选择共同给药的未标记抗体剂量，可以实现放射性抗体更均匀的分布。 目前正在进行工作，以确定放射性抗体的改善肿瘤分布对单剂量放射性抗体的治疗潜力的影响。
The inaccessibility of radiolabeled antibody to poorly vascularized regions of solid tumors may reduce the therapeutic efficacy of these macromolecules. Theoretical mathematical models have predicted that increasing the protein dose administered would reduce the heterogeneity of radioantibody distribution. This investigation was undertaken to evaluate this hypothesis in experimental animal models. We have utilized the technique of macroautoradiography to demonstrate an increase in tumor penetration of the lower-affinity I-125-labeled NP-4 or higher-affinity Immu-14 anti-carcinoembryonic antigen (anti-CEA) mAbs into small (60.25-0.4 g) and large (0.8-1.5 g) GW-39 and LS174T human colonic xenografts, grown subcutaneously in the nude mouse, when 400-mu-g unlabeled antibody is administered simultaneously with 10-mu-g (100-mu-Ci) radioantibody. Further increases in protein to 800-mu-g result in a reduction in total tumor uptake of the antibody. These differences in mAb distribution could be visualized as early as 1 day after antibody injection. Improved mAb penetration was also achieved for the Mu-9 anti-CSAp (anti-mucin) antibody using 800-mu-g unlabeled antibody. An irrelevant antibody (AFP-7-31) was found to be homogeneously distributed 3 days after injection, even at a low protein dose. Attempts to improve mAb penetration by increasing the protein dose in the GS-2 colorectal tumor, a model that has low NP-4 accretion as a result physiological barriers separating antibody from antigen, were not successful. These results suggest that a more homogeneous distribution of radioantibody can be achieved by carefully selecting a dose of unlabeled antibody to coadminister. Work is currently in progress to determine the effect of improved tumor distribution of radioantibody on the therapeutic potential of a single dose of radioantibody.