Biodistribution and pharmacokinetics of 125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX, an intrinsic marker of hypoxia, in nude mice xenografted with human colorectal carcinoma
Biodistribution and pharmacokinetics of 125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX, an intrinsic marker of hypoxia, in nude mice xenografted with human colorectal carcinoma
复制标题
DOI：
10.1002/ijc.11142
复制
发表时间：
2003-07-20
影响因子：
6.4
通讯作者：
Pastoreková, S
中科院分区：
文献类型：
--
作者：
Chrastina, A;Závada, J;Pastoreková, S
碳酸酐酶IX（CA IX）在人类肿瘤中频繁表达，而在相应的正常组织中不表达。肿瘤缺氧的强烈诱导使CA IX倾向于作为癌症诊断和治疗的靶点。在这里，我们评估了CA IX特异性单克隆抗体（MAb）M75的靶向特性和药代动力学。在体外分析了I-125标记的M75的结合参数，包括平衡解离常数、与各种细胞系的缺氧相关结合和内化。用组织切片放射性测定和组织切片宏观放射自显影研究了I-125-M75 i在荷HT-29人大肠癌裸鼠体内的生物分布。使用二室模型描述了静脉给药I-125- M75的药代动力学。注射后血液清除率显示分布相t（1/2）（α）= 3.4 h，消除相t（1/2）（0）= 55.3 h。尽管CA IX主要定位于不易接近的坏死周围区域，但I-125-M75在异种移植物中表现出特异性蓄积，给药后48小时每克肿瘤组织平均摄取15.3 +/- 3.6%注射剂量。通过对照抗体的低肿瘤摄取证实了M75定位的特异性。总之，我们的数据表明，M75单抗是一种有前途的工具，用于选择性免疫靶向表达CA IX（C）的缺氧人类肿瘤2003 Wiley-Liss，Inc。
Carbonic anhydrase IX (CA IX) is frequently expressed in human carcinomas and absent from the corresponding normal tissues. Strong induction by tumor hypoxia predisposes CA IX to serve as a target for cancer diagnostics and therapy. Here we evaluated targeting properties and pharmacokinetics of CA IX-specific monoclonal antibody (MAb) M75. Binding parameters of I-125-labeled M75, including equilibrium dissociation constant, hypoxia-related binding to various cell lines and internalization, were analyzed in vitro. Biodistribution of I-125-M75 i in nude mice bearing HT-29 human colorectal carcinoma xenografts with hypoxic pattern of CA IX expression was studied by measurements of radioactivity in dlissected tissues and macroautoradiography of tissue sections. Pharmacokinetics of intravenously administered I-125- M75 was described using a 2-compartment model. Blood clearance showed a distribution phase t(1/2)(alpha) = 3.4 hr and an elimination phase t(1/2)(0) = 55.3 hr postinjection. Despite predominant CA IX localization in less accessible perinecrotic regions, I-125-M75 exhibited specific accumulation in xenograft, with a mean uptake of 15.3 +/- 3.6% of injected dose per gram of tumor tissue at 48 hr postadministration. Specificity of M75 localization was confirmed by low tumor uptake of control antibody. Altogether, our data demonstrate that M75 MAb is a promising tool for selective immunotargeting of hypoxic human tumors that express CA IX (C) 2003 Wiley-Liss, Inc.