Mulligan T, Carrasquillo J A, Chung Y, Milenic D E, Schlom J, Feuerstein I, Paik C, Perentesis P, Reynolds J, Curt G
Medicine Branch, Laboratory of Tumor Immunology & Biology, Division of Cancer Biology & Diagnosis, National Cancer Institute, Clinical Center, NIH, Bethesda, Maryland 20982, USA.
Clin Cancer Res. 1995 Dec;1(12):1447-54.
CC49, a murine monoclonal antibody that recognizes the tumor-associated glycoprotein 72, was conjugated to the chemical chelate 1,4,7,10-tetraaza-1-(1-carboxy-3-(4-aminophenyl) propyl)-tris-4,7,10- ((carboxy)methyl)cyclododecane that had been labeled with a beta emitter, Lu. Preclinical studies had shown that Lu-labeled CC49 caused regression of human colon adenocarcinoma xenografts in nude mice. Patients with advanced adenocarcinoma who had failed standard treatment and whose tumors expressed the tumor-associated glycoprotein 72 antigen were eligible for treatment to determine the maximum tolerated dose of Lu-labeled CC49. The starting dose of Lu was 10 mCi/m2 given i.v. with the dose of CC49 held constant at 20 mg. Pharmacokinetic sampling and immunoscintigraphy were performed over the ensuing 3 weeks. The dose of radioactive Lu was escalated by 15 mCi/m2 for each successive dose level. Unexpected bone marrow toxicity developed in patients treated at the second dose level with 25 mCi/m2 Lu; two patients developed grade 4 thrombocytopenia, while the third patient developed grade 3 thrombocytopenia. Pharmacokinetic studies showed that the plasma half-life of the immunoconjugate was 67 h; whole-body retention, however, was prolonged with a biological half-life of 258 h. Serial gamma camera imaging localized known tumor in all patients, and also demonstrated prolonged Lu retention in the reticuloendothelial system (RES). Bone marrow dosimetry estimates ranged from 4 to 5 REMS/mCi Lu based on imaging and biopsy data. Analysis of bone marrow biopsies demonstrated that most of the Lu was localized in the cellular compartment and not in the bone. No antitumor responses were observed. Intravenous administration of 15 mCi/m2 Lu-labeled CC49 to previously treated advanced cancer patients was associated with acceptable hematological toxicity and was the maximum tolerated dose. However, prolonged retention of Lu in the RES, including the bone marrow, was observed and limited the dose of Lu that could be given. Additional studies are indicated to reduce RES uptake and retention of this immunoconjugate.
CC49是一种识别肿瘤相关糖蛋白72的鼠单克隆抗体，它与化学螯合物1,4,7,10-四氮杂-1-(1-羧基-3-(4-氨基苯基)丙基)-三-4,7,10-((羧基)甲基)环十二烷缀合，该螯合物已用β发射体镥进行标记。临床前研究表明，镥标记的CC49可使裸鼠体内的人结肠腺癌异种移植瘤消退。标准治疗失败且肿瘤表达肿瘤相关糖蛋白72抗原的晚期腺癌患者有资格接受治疗，以确定镥标记的CC49的最大耐受剂量。镥的起始剂量为10毫居里/平方米，静脉注射，CC49的剂量保持在20毫克不变。在随后的3周内进行药代动力学采样和免疫闪烁显像。每一个连续的剂量水平，放射性镥的剂量递增15毫居里/平方米。在接受25毫居里/平方米镥治疗的第二剂量水平的患者中出现了意外的骨髓毒性；两名患者出现4级血小板减少，而第三名患者出现3级血小板减少。药代动力学研究表明，免疫缀合物的血浆半衰期为67小时；然而，全身滞留时间延长，生物半衰期为258小时。连续的γ相机成像在所有患者中定位了已知肿瘤，并且还显示镥在网状内皮系统（RES）中滞留时间延长。根据成像和活检数据，骨髓剂量估计范围为4至5雷姆/毫居里镥。骨髓活检分析表明，大部分镥定位于细胞区室而非骨骼中。未观察到抗肿瘤反应。对先前治疗的晚期癌症患者静脉注射15毫居里/平方米镥标记的CC49与可接受的血液学毒性相关，这是最大耐受剂量。然而，观察到镥在RES（包括骨髓）中滞留时间延长，限制了可给予的镥剂量。需要进行更多研究以减少这种免疫缀合物在RES中的摄取和滞留。
