Schlom J, Siler K, Milenic D E, Eggensperger D, Colcher D, Miller L S, Houchens D, Cheng R, Kaplan D, Goeckeler W
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cancer Res. 1991 Jun 1;51(11):2889-96.
177Lutetium (177Lu) is a member of the family of elements known as lanthanides or rare earths. Monoclonal antibody (MAb) CC49, a murine IgG1, which is reactive with the tumor-associated antigen, TAG-72, has been shown previously to react with a wide range of human carcinomas; CC49 reacts to a different epitope on the TAG-72 molecule than MAb B72.3 and has a higher binding affinity. We report here the first use of a 177Lu-labeled immunoconjugate, 177Lu-CC49, in an experimental therapy model for human carcinoma. 177Lu-CC49 was shown to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Overt toxicity was observed with the administration of approximately 500 microCi of 177Lu-CC49 in which 5 of 9 mice died of apparent marrow toxicity. A single administration of 200 or 350 microCi of 177Lu-CC49, however, was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 microCi of 177Lu-CC49 (250 microCi/week for 3 consecutive weeks) was well tolerated in that 9 of 10 mice survived. Moreover, this dose schedule was able to eliminate the growth of relatively large (300 mm3) human colon tumor xenografts in 90% of the animals treated. Single-dose and dose fractionation studies were also carried out with an isotype-matched control MAb, 177Lu-MOPC-21. In all dose schedules, a large differential was seen between the therapeutic effects of the 177Lu-CC49 versus that of the 177Lu-control MAb. The merits and limitations of the use of 177Lu-labeled immunoconjugates (in particular, 177Lu-CC49) are discussed in terms of potential novel therapeutics for human carcinoma.
镥-177（177Lu）是镧系元素或稀土元素家族的一员。单克隆抗体（MAb）CC49是一种鼠IgG1，可与肿瘤相关抗原TAG-72发生反应，此前已证明它能与多种人类癌症发生反应；CC49与TAG-72分子上的一个不同表位发生反应，与单克隆抗体B72.3不同，且具有更高的结合亲和力。我们在此报告首次在人类癌症的实验治疗模型中使用177Lu标记的免疫缀合物177Lu-CC49。结果显示，单剂量50微居里的177Lu-CC49可延缓无胸腺小鼠体内已形成的LS-174T人结肠癌的生长。给予约500微居里的177Lu-CC49时观察到明显毒性，9只小鼠中有5只因明显的骨髓毒性死亡。然而，单剂量给予200或350微居里的177Lu-CC49，在给予单克隆抗体后的77天观察期内可使已形成的肿瘤消除。剂量分割实验表明，至少750微居里的177Lu-CC49（连续3周每周250微居里）耐受性良好，10只小鼠中有9只存活。此外，该剂量方案能够使90%接受治疗的动物体内相对较大（300立方毫米）的人结肠肿瘤异种移植物的生长消除。还使用同型匹配的对照单克隆抗体177Lu-MOPC-21进行了单剂量和剂量分割研究。在所有剂量方案中，177Lu-CC49与177Lu对照单克隆抗体的治疗效果之间存在很大差异。从人类癌症潜在的新型治疗方法角度讨论了使用177Lu标记的免疫缀合物（特别是177Lu-CC49）的优点和局限性。
