Williams J A, Wessels B W, Wharam M D, Order S E, Wanek P M, Poggenburg J K, Klein J L
Division of Radiation Oncology, Johns Hopkins Oncology Center, Baltimore, MD 21205.
Int J Radiat Oncol Biol Phys. 1990 Jun;18(6):1367-75. doi: 10.1016/0360-3016(90)90310-g.
Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal and polyclonal 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. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (microCi) of tumor activity per gram per 100 microCi injected activity compared to 4.5 microCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The proportion of tumor dose found in normal organs is less than 10%, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, and polyclonal rabbit antiferritin, which defines a tumor-associated antigen, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. When compared to the 111In-radiolabeled antibody, 90Y-radiolabeled P96.5 demonstrates comparable tumor targeting and percentages of tumor dose found in normal organs. To test the therapeutic potential of 90Y-radiolabeled P96.5, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Seven days following administration of 100 microCi 90Y-radiolabeled P96.5, average absorbed doses of 3770, 980, 353, and 274 cGy were observed in tumor, liver, contralateral control site, and total body, respectively. Shared cell surface antigens among neuroectodermally derived neoplasms provide a basis for exploration of human glioma radioimmunotherapy.
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和多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。与注射放射性标记的无关单克隆抗体后每克肿瘤活性为4.5微居里相比，111In标记的P96.5能特异性靶向U-251人胶质瘤异种移植瘤，每100微居里注射活性可产生87.0微居里的肿瘤活性。靶向率计算表明，与无关单克隆抗体相比，注射放射性标记的P96.5后沉积剂量高出11.6倍。在正常器官中发现的肿瘤剂量比例小于10%，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。定义第二种黑色素瘤相关抗原的单克隆抗体ZME018和定义一种肿瘤相关抗原的多克隆兔抗铁蛋白，显示出肿瘤的阳性免疫过氧化物酶染色，但靶向性相对降低。与111In标记的抗体相比，90Y标记的P96.5显示出相当的肿瘤靶向性以及在正常器官中发现的肿瘤剂量百分比。为了测试90Y标记的P96.5的治疗潜力，在肿瘤和正常部位植入了微型热释光剂量计（TLD）。注射100微居里90Y标记的P96.5七天后，在肿瘤、肝脏、对侧对照部位和全身分别观察到平均吸收剂量为3770、980、353和274 cGy。神经外胚层来源肿瘤之间共享的细胞表面抗原为探索人类胶质瘤放射免疫治疗提供了基础。
