Koppe Manuel J, Soede Annemieke C, Pels Wikke, Oyen Wim J G, Goldenberg David M, Bleichrodt Robert P, Boerman Otto C
Department of Surgery, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Int J Cancer. 2003 Oct 10;106(6):965-72. doi: 10.1002/ijc.11304.
Radioimmunotherapy using radiolabeled monoclonal antibodies (MoAbs) directed against tumor-associated antigens might be an effective treatment modality for small volume disease. Our aim was to optimize an experimental model of radioimmunotherapy for small peritoneal metastases of colorectal origin using the anti-CEA MoAb MN-14. In nude mice with intraperitoneal (i.p.) LS174T tumors, a protein dose-escalation study was carried out to determine the maximal dose of radioiodinated MN-14 to be used in radioimmunotherapy. The biodistribution of radioiodinated MN-14 was determined after intravenous (i.v.) and i.p. administration. Finally, the therapeutic efficacy of escalating activity doses of (131)I-labeled MN-14 (62.5-500 microCi) was assessed and compared to that of unlabeled MN-14 or 500 microCi of (131)I-labeled irrelevant control antibody. At protein doses higher than 25 microg, uptake in tumor was reduced, presumably due to saturation of tumor antigen. During the first 24 hours i.p. administration led to higher tumor uptake and higher tumor:blood ratios than i.v. administration. Median survival of the control groups was 38 days (unlabeled MN-14) and 52 days ((131)I-labeled nonspecific antibody). Median survival of the groups treated with increasing activity doses of (131)I-labeled MN-14 was 42 days (62.5 microCi), 49 days (125 microCi), 63 days (250 microCi) and 101 days (500 microCi), respectively (p < 0.0001 compared to unlabeled MN-14). The present study shows that the anti-CEA-antibody MN-14 preferentially accumulates in i.p. LS174T tumor xenografts after both i.p. and i.v. administration. Intraperitoneal radioimmunotherapy using (131)I-labeled MN-14 delays significantly the outgrowth of peritoneal LS174T metastases, even at relatively low activity doses.
使用针对肿瘤相关抗原的放射性标记单克隆抗体（MoAb）进行放射免疫治疗可能是一种针对小体积疾病的有效治疗方式。我们的目标是利用抗癌胚抗原（CEA）单克隆抗体MN-14优化针对结直肠来源的小腹膜转移瘤的放射免疫治疗实验模型。在患有腹腔内（i.p.）LS174T肿瘤的裸鼠中，进行了蛋白质剂量递增研究，以确定放射免疫治疗中使用的放射性碘化MN-14的最大剂量。在静脉内（i.v.）和腹腔内给药后，测定放射性碘化MN-14的生物分布。最后，评估了递增活性剂量的（131）I标记的MN-14（62.5 - 500微居里）的治疗效果，并与未标记的MN-14或500微居里的（131）I标记的无关对照抗体的治疗效果进行比较。在蛋白质剂量高于25微克时，肿瘤摄取减少，推测是由于肿瘤抗原饱和所致。在最初的24小时内，腹腔内给药比静脉内给药导致更高的肿瘤摄取和更高的肿瘤与血液比值。对照组的中位生存期为38天（未标记的MN-14）和52天（（131）I标记的非特异性抗体）。用递增活性剂量的（131）I标记的MN-14治疗的组的中位生存期分别为42天（62.5微居里）、49天（125微居里）、63天（250微居里）和101天（500微居里）（与未标记的MN-14相比，p < 0.0001）。本研究表明，抗CEA抗体MN-14在腹腔内和静脉内给药后均优先积聚在腹腔内LS174T肿瘤异种移植物中。使用（131）I标记的MN-14进行腹腔内放射免疫治疗即使在相对较低的活性剂量下也能显著延迟腹膜LS174T转移瘤的生长。
