Aarts Frits, Hendriks Thijs, Eek Annemarie, Oyen Wim J G, Bleichrodt Robert P, Boerman Otto C
Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Cancer Biother Radiopharm. 2009 Feb;24(1):29-34. doi: 10.1089/cbr.2008.0521.
In radioimmunotherapy (RIT), hematologic toxicity is the dose-limiting toxicity due to the long circulatory half-life of the antibody. Although intraperitoneal (i.p.) RIT results in high uptake of i.p. growing tumors, the radiolabeled antibody enters the circulation, resulting in bone marrow toxicity. Carbohydrate modification of antibodies could induce accelerated clearance of the antibody via the hepatic asialoglycoprotein receptor, thereby reducing exposure to normal tissues. In this study, we investigated whether galactosylation of an antibody in a model of peritoneal carcinomatosis (PC) of colonic origin could be used to improve targeting of i.p. growing tumors. Therefore, the biodistribution of the galactosylated and nongalactosylated anti-CC531 antibody, MG1, after i.p. injection was determined in a model of peritoneal carcinomatosis of CC-531 colon tumors in Wag/Rij rats. Uptake of the radiolabeled antibodies in the tumor and relevant organs was determined at 2, 4, 24, and 48 hours after injection. Galactosylation of the antibody did not affect the binding affinity of MG1. Remarkably, the uptake of Gal-MG1 in tumors was higher than that of MG1 at 2 and 4 hours after injection. After 24 and 48 hours, uptake of Gal-MG1 in tumor tissue was lower than that of MG1. Gal-MG1 cleared from the blood within hours after administration. At 2-24 hours after administration, tumor-to-blood ratios obtained with Gal-MG1 were significantly higher than those obtained with unmodified MG1. Antibody galactosylation resulted in improved tumor-non-tumor ratios after i.p. injection in a model of PC. This could improve the efficiency of RIT, especially in combination with short-lived nonresidualizing radionuclides.
在放射免疫疗法（RIT）中，由于抗体的循环半衰期较长，血液学毒性是剂量限制性毒性。尽管腹腔内（i.p.）放射免疫疗法可使腹腔内生长的肿瘤大量摄取，但放射性标记的抗体进入循环系统会导致骨髓毒性。抗体的碳水化合物修饰可通过肝脏去唾液酸糖蛋白受体诱导抗体加速清除，从而减少对正常组织的暴露。在本研究中，我们调查了在结肠源性腹膜癌（PC）模型中，抗体的半乳糖基化是否可用于改善对腹腔内生长肿瘤的靶向性。因此，在Wag/Rij大鼠的CC-531结肠肿瘤腹膜癌模型中，测定了腹腔注射后半乳糖基化和非半乳糖基化抗CC531抗体MG1的生物分布。在注射后2、4、24和48小时测定肿瘤及相关器官中放射性标记抗体的摄取情况。抗体的半乳糖基化不影响MG1的结合亲和力。值得注意的是，注射后2小时和4小时，Gal-MG1在肿瘤中的摄取高于MG1。24小时和48小时后，Gal-MG1在肿瘤组织中的摄取低于MG1。Gal-MG1在给药后数小时内从血液中清除。给药后2至24小时，Gal-MG1的肿瘤与血液比值显著高于未修饰的MG1。在PC模型中，抗体半乳糖基化导致腹腔注射后肿瘤与非肿瘤比值提高。这可提高放射免疫疗法的效率，尤其是与短寿命非残留放射性核素联合使用时。
