Schneider-Gädicke E, Humm J L, Lau C C, Macklis R M, Bastert G, Knapp R C
Division of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Radiother Oncol. 1992 Mar;23(3):150-9. doi: 10.1016/0167-8140(92)90325-o.
Monoclonal antibody (mAb) OC125 detects the cell surface-antigen CA125, which is expressed in more than 80% of epithelial ovarian cancers but not in normal adult ovaries. Its high specificity and binding affinity makes OC125 a potential candidate for use in radioimmunotherapy (RIT) in patients with recurrent ovarian cancer. Initial biodistribution studies using radiolabelled specific mAbs have demonstrated significant increase in tumor uptake of dose as compared to radiolabelled irrelevant antibody. We report here an isodose comparison of the cytotoxicity of 131I-labelled OC125 F(ab')2, 131I-labelled nonspecific protein and external beam irradiation using a cesium-137 gamma source. Enhancement of cytotoxity due to the specific binding of the mAb could only be observed when a critical activity of 131I localized at the cell membrane. At a specific activity labelling of less than 4.1 mCi/mg, the antigen specificity of OC125 does not contribute to cell kill. Using a specific activity of 10.2 mCi/mg, the relative biological effectiveness of 131I-labelled OC125 (F(ab')2 was increased by a factor of 5 compared with external-beam X-ray therapy, and the specificity of mAb OC125 was found to enhance the cytotoxicity of the radioimmunoconjugate (RIC) by a factor of 2.7. This low value is in accordance with previously reported theoretical calculations for long range, low-LET isotopes and may be one of the reasons why RIT using 131I has severe limitations. In conclusion, it is necessary to maximize the specific activity of RICs with low-LET isotopes such as iodine-131 in order to maximize the ratio of the dose delivered specifically by membrane-bound mAb versus free-floating nonspecific protein.
单克隆抗体（mAb）OC125可检测细胞表面抗原CA125，该抗原在80%以上的上皮性卵巢癌中表达，但在正常成年卵巢中不表达。其高特异性和结合亲和力使OC125成为复发性卵巢癌患者放射免疫治疗（RIT）的潜在候选药物。最初使用放射性标记特异性单克隆抗体的生物分布研究表明，与放射性标记的无关抗体相比，肿瘤对剂量的摄取显著增加。我们在此报告使用铯-137γ源对131I标记的OC125 F(ab')2、131I标记的非特异性蛋白和外照射的细胞毒性进行的等剂量比较。只有当131I的关键活性定位于细胞膜时，才能观察到由于单克隆抗体的特异性结合而导致的细胞毒性增强。在比活度标记小于4.1 mCi/mg时，OC125的抗原特异性对细胞杀伤没有贡献。使用10.2 mCi/mg的比活度，与外照射X线治疗相比，131I标记的OC125（F(ab')2的相对生物学效应增加了5倍，并且发现单克隆抗体OC125的特异性使放射免疫偶联物（RIC）的细胞毒性增强了2.7倍。这个低值与先前报道的关于长程、低LET同位素的理论计算结果一致，这可能是使用131I进行RIT存在严重局限性的原因之一。总之，有必要使低LET同位素（如碘-131）的RIC比活度最大化，以最大化膜结合单克隆抗体特异性递送的剂量与游离非特异性蛋白剂量的比值。
