Williams J A, Wessels B W, Edwards J A, Kopher K A, Wanek P M, Wharam M D, Order S E, Klein J L
Division of Radiation Oncology, Johns Hopkins Oncology Center, Baltimore, Maryland 21205.
Cancer Res. 1990 Feb 1;50(3 Suppl):974s-979s.
Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. IIIIn-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCi of tumor activity/g/100 microCi injected activity compared to 4.5 microCi following administration of 100 microCi radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate the deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The dose found in normal organs is less than 20% of that in the tumor, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, demonstrates positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5 and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters. Average absorbed doses of 3770 +/- 445 (SEM) and 645 +/- 48 cGy in tumor, 353 +/- 41 and 222 +/- 13 cGy in a contralateral control i.m. site, 980 +/- 127 and 651 +/- 63 cGy in liver, and 275 +/- 14 and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 microCi 90Y-radiolabeled P96.5 and ZME018, respectively. Calculations of absorbed dose by the medical internal radiation dose method confirmed thermoluminescent dosimeter absorbed dose measurements. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or 90Y-radiolabeled P96.5 or ZME018. Tumor regression was measured in 1 of 12, 9 of 10, and 12 of 12 compared to 0 of 10, 1 of 10, and 2 of 10 animals following administration of 50, 100, or 200 microCi 90Y-labeled P96.5 and ZME018, respectively. Average maximal decreases in tumor volume were 42.7 +/- 11.9 and 94.2 +/- 3.3% 28 and 58 days following 100 and 200 microCi 90Y-radiolabeled P96.5 administration, respectively. In contrast, no average decrease in tumor volume was noted following 50, 100, or 200 microCi 90Y-labeled ZME018.(ABSTRACT TRUNCATED AT 400 WORDS)
放射性标记抗体为人类胶质瘤的选择性放射治疗提供了潜在基础。我们已在携带人胶质瘤异种移植瘤的裸鼠中，测量了针对神经外胚层和肿瘤相关抗原的放射性标记单克隆抗体的肿瘤靶向性。单克隆抗体P96.5是一种小鼠IgG2a免疫球蛋白，可识别一种人类黑色素瘤细胞表面蛋白的表位，通过免疫过氧化物酶组织化学检测，它能特异性结合U-251人胶质瘤。铟-111放射性标记的P96.5特异性靶向U-251人胶质瘤异种移植瘤，每克肿瘤活性为87.0微居里/100微居里注射活性，而注射100微居里放射性标记的无关单克隆抗体后每克肿瘤活性为4.5微居里。靶向率计算表明，与无关单克隆抗体相比，放射性标记的P96.5给药后沉积剂量高11.6倍。在正常器官中发现的剂量不到肿瘤中剂量的20%，这进一步支持了该抗体对人胶质瘤异种移植瘤的特异性靶向作用。单克隆抗体ZME018可识别另一种黑色素瘤相关抗原，肿瘤免疫过氧化物酶染色呈阳性，但靶向性相对降低。为了测试钇-90放射性标记的P96.5和ZME018的治疗潜力，在肿瘤和正常部位植入了微型热释光剂量计。分别给予100微居里钇-90放射性标记的P96.5和ZME018后7天，肿瘤的平均吸收剂量分别为3770±445（标准误）和645±48厘戈瑞，对侧对照肌肉部位为353±41和222±13厘戈瑞，肝脏为980±127和651±63厘戈瑞，全身为275±14和256±18厘戈瑞。通过医学内照射剂量法计算的吸收剂量证实了热释光剂量计的吸收剂量测量结果。为了测试治疗潜力，给荷瘤裸鼠心脏内注射缓冲液或钇-90放射性标记的P96.5或ZME018。与分别给予50、100或200微居里钇-90标记的P96.5和ZME018后10只动物中有0只、1只和2只肿瘤消退相比，12只动物中有1只、10只动物中有9只和12只动物中有12只肿瘤消退。分别给予100和200微居里钇-90放射性标记的P96.5后28天和58天，肿瘤体积的平均最大减小分别为42.7±11.9%和94.2±3.3%。相比之下，给予50、100或200微居里钇-90标记的ZME018后，肿瘤体积未见平均减小。（摘要截短于400字）
