Schott M E, Schlom J, Siler K, Milenic D E, Eggensperger D, Colcher D, Cheng R, Kruper W J, Fordyce W, Goeckeler W
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Cancer. 1994 Feb 1;73(3 Suppl):993-8. doi: 10.1002/1097-0142(19940201)73:3+<993::aid-cncr2820731337>3.0.co;2-7.
Lutetium-177 (177Lu), samarium-153 (153Sm), and yttrium-90 (90Y) are members of the family of elements known as lanthanides or rare earths. Monoclonal antibody CC49, a murine immunoglobulin (Ig) G1, which is reactive with the tumor-associated antigen TAG-72, previously has been shown to react with a wide range of human carcinomas. The authors review here the comparative biodistributions of CC49 IgG and F(ab')2 fragments labeled with 177Lu, 153Sm, and 90Y using the bifunctional chelating agent PA-DOTA. The authors also review the results of a biodistribution study comparing iodine-125-labeled and 177Lu-labeled CC49 sFv, and the use of 177Lu-CC+9 IgG in an experimental therapy model. Chelation and conjugations gave similar yields, and the labeled proteins showed similar retention of immunoreactivity regardless of the isotope used for both IgG and F(ab')2. Biodistribution data obtained in athymic mice bearing LS-174T human colon carcinoma xenografts likewise showed no differences among the three radioisotopes for both IgG and F(ab')2. Femur uptake of radioactivity was lower than previously reported for other radiolanthanide immunoconjugates. Different metabolic patterns were observed for radioiodinated versus radiometal-labeled sFv, particularly in the kidney, where localization of the latter was increased dramatically. 177Lu-CC49 was found to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Elimination of established tumors was demonstrated over the observation period (77 days) using single administrations of 200 or 350 microCi. Dose fractionation experiments revealed that the mice tolerated 750 microCi (3 x 250 microCi, given weekly), whereas > 50% of the mice died after receiving a single administration of approximately 500 microCi. In isotype-matched control experiments, a large differential in the therapeutic effects was observed between 177Lu-labeled control antibody and CC49.
镥 - 177（177Lu）、钐 - 153（153Sm）和钇 - 90（90Y）是被称为镧系元素或稀土元素家族的成员。单克隆抗体CC49是一种鼠源免疫球蛋白（Ig）G1，它与肿瘤相关抗原TAG - 72发生反应，此前已被证明能与多种人类癌组织发生反应。作者在此回顾了使用双功能螯合剂PA - DOTA标记的177Lu、153Sm和90Y的CC49 IgG和F(ab')2片段的比较生物分布情况。作者还回顾了一项生物分布研究的结果，该研究比较了碘 - 125标记和177Lu标记的CC49单链抗体片段（sFv），以及177Lu - CC + 9 IgG在实验治疗模型中的应用。螯合和偶联反应产率相似，且无论用于IgG和F(ab')2的同位素如何，标记后的蛋白质都显示出相似的免疫反应性保留情况。在携带LS - 174T人结肠癌异种移植瘤的无胸腺小鼠中获得的生物分布数据同样显示，对于IgG和F(ab')2，这三种放射性同位素之间没有差异。股骨对放射性的摄取低于先前报道的其他放射性镧系免疫缀合物。观察到放射性碘标记与放射性金属标记的sFv有不同的代谢模式，特别是在肾脏，后者在肾脏中的定位显著增加。发现单剂量50微居里的177Lu - CC49可延缓无胸腺小鼠中已建立的LS - 174T人结肠癌的生长。在观察期（77天）内，通过单次给予200或350微居里证明了已建立肿瘤的消除。剂量分割实验表明，小鼠耐受750微居里（3×250微居里，每周给药），而在接受单次约500微居里给药后，超过50%的小鼠死亡。在同型对照实验中，观察到177Lu标记的对照抗体与CC49之间在治疗效果上有很大差异。
