Manske J M, Buchsbaum D J, Hanna D E, Vallera D A
Department of Therapeutic Radiology, University of Minnesota, Minneapolis 55455.
Cancer Res. 1988 Dec 15;48(24 Pt 1):7107-14.
An immunoconjugate, consisting of both toxin and radionuclide on the same antibody molecule, was synthesized by cross-linking the phytotoxin ricin to the T101 monoclonal antibody recognizing the CD5 cluster expressed on normal and malignant T-cells. The hybrid molecule was then labeled with iodine-125 by an iodine monochloride procedure. This radioimmunotoxin (RIT), which selectively bound to the CD5-positive CEM human leukemia cell line, was selectively inhibitory to antigen-positive cells in protein synthesis inhibition assays. RIT was only 3.0-7.8-fold less toxic and was 1.1-1.6-fold slower than unlabeled immunotoxin in inhibiting protein synthesis. Because of the radionuclide moiety, the RIT also provided information related to biodistribution and pharmacokinetics. Four days following intratumoral injection, more than 125-fold greater activity was found in CEM tumors implanted in nude mice as compared to normal tissues. The mean blood half-life for RIT was 25.7 h and for radiolabeled antibody, 91.3 h. Intratumoral injections of RIT selectively induced regression of established CEM tumors. To our knowledge, these studies are the first to demonstrate that a single immunoconjugate can combine the advantages of both a catalytic toxin and radionuclide for cancer therapy.
通过将植物毒素蓖麻毒素与识别正常和恶性T细胞上表达的CD5簇的T101单克隆抗体交联，合成了一种免疫缀合物，该免疫缀合物在同一抗体分子上同时含有毒素和放射性核素。然后通过一氯化碘法用碘-125对该杂合分子进行标记。这种放射免疫毒素（RIT）选择性地结合CD5阳性的CEM人白血病细胞系，在蛋白质合成抑制试验中对抗原阳性细胞具有选择性抑制作用。RIT的毒性仅比未标记的免疫毒素低3.0 - 7.8倍，在抑制蛋白质合成方面比未标记的免疫毒素慢1.1 - 1.6倍。由于放射性核素部分，RIT还提供了与生物分布和药代动力学相关的信息。瘤内注射后四天，与正常组织相比，植入裸鼠的CEM肿瘤中的活性高出125倍以上。RIT的平均血液半衰期为25.7小时，放射性标记抗体的平均血液半衰期为91.3小时。瘤内注射RIT可选择性地诱导已形成的CEM肿瘤消退。据我们所知，这些研究首次证明单一免疫缀合物可结合催化毒素和放射性核素两者的优势用于癌症治疗。
