Tsukada Y, Ohkawa K, Hibi N, Tsuzuki K, Oguma K, Satoh H
Research Department, Special Reference Laboratory Inc., Tokyo, Japan.
Cancer Biochem Biophys. 1989 May;10(3):247-56.
A monoclonal mouse antibody (MoHG) was produced using in vitro cultured AH66R tumor cells treated with cholesteryl hemisuccinate as an immunogen. The antibody identified a 90 kd membrane glycoprotein (HG-90) which is expressed on in vitro cultured hepatoma cell lines AH66 and AH66R. A monoclonal antibody was prepared to the anthracycline drug daunomycin, and it also reacted with adriamycin. A fusion was made of the hybridoma HG-90 with the hybridoma which recognized daunomycin/adriamycin. This bispecific hybridoma A8C recognized both determinants. We studied the therapeutic effect of the A8C bispecific antibody with adriamycin treatment and compared it to the effect of the bispecific antibody to which adriamycin had been conjugated via an albumin (Alb) bridge. The therapy model used was the tumor AH66R in Donryu rats. Tumor bearing rats had their subcutaneous tumors resected on day 10, a time when distant metastases were present. After the surgical resection of the tumor the rats were injected intravenously for two cycles with the bispecific antibodies, followed by the administration of adriamycin (ADR) or MoHG.Alb.ADR conjugates. A slight therapeutic effect occurred with either MoHG or ADR alone but treatment with the bispecific antibody followed by the administration of ADR or with the MoHG.Alb.ADR conjugates significantly prolonged survival, with 60% of the treated animals being "tumor free" when sacrificed on day 80. Lower serum concentrations of alphafetoprotein were observed with the bispecific antibody and drug treatment. This suggests that the bispecific antibody/drug treatment is potentially more beneficial in the suppression of distant metastases than the MoHG.Alb.ADR conjugate. This may be due to an increase in the local drug concentration of unmodified adriamycin.
以经胆固醇半琥珀酸酯处理的体外培养AH66R肿瘤细胞作为免疫原，制备了一种单克隆小鼠抗体（MoHG）。该抗体识别一种90kd的膜糖蛋白（HG - 90），其在体外培养的肝癌细胞系AH66和AH66R上表达。制备了针对蒽环类药物柔红霉素的单克隆抗体，它也与阿霉素发生反应。将杂交瘤HG - 90与识别柔红霉素/阿霉素的杂交瘤进行融合。这种双特异性杂交瘤A8C识别两种决定簇。我们研究了A8C双特异性抗体联合阿霉素治疗的效果，并将其与通过白蛋白（Alb）桥连接阿霉素的双特异性抗体的效果进行比较。所使用的治疗模型是Donryu大鼠体内的AH66R肿瘤。荷瘤大鼠在第10天进行皮下肿瘤切除，此时已出现远处转移。肿瘤手术切除后，大鼠静脉注射双特异性抗体两个周期，随后给予阿霉素（ADR）或MoHG.Alb.ADR偶联物。单独使用MoHG或ADR时出现轻微治疗效果，但双特异性抗体联合ADR治疗或使用MoHG.Alb.ADR偶联物可显著延长生存期，80天时处死的动物中有60%“无肿瘤”。双特异性抗体与药物治疗组观察到较低的血清甲胎蛋白浓度。这表明双特异性抗体/药物治疗在抑制远处转移方面可能比MoHG.Alb.ADR偶联物更有益。这可能是由于未修饰的阿霉素局部药物浓度增加所致。
