Yokota T, Milenic D E, Whitlow M, Wood J F, Hubert S L, Schlom J
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cancer Res. 1993 Aug 15;53(16):3776-83.
In previous studies, we have compared the immunochemical properties, the in vivo pharmacokinetics, and the tumor penetrance of a radioiodinated single-chain Fv (sFv) in comparison with other immunoglobulin (Ig) forms (intact IgG, F(ab')2, and Fab') (Cancer Res., 51: 6363-6371, 1991). Biodistribution studies demonstrated a higher percent injected dose/g in the liver and spleen for the intact IgG and F(ab')2. Renal uptake was observed with the Fab' and F(ab')2, whereas the sFv demonstrated no specific localization in either of these organs. The 125I-labeled sFv also demonstrated a more even distribution throughout the tumor xenografts as compared to the other Ig forms (Cancer Res., 52: 3402-3408, 1992). Subsequent studies utilizing the sFv conjugated with a radiometal (177Lu) demonstrated that the sFv was being metabolized by the kidney, and a significantly higher percent injected dose/g was obtained with a 177Lu-labeled sFv as compared to a 125I-labeled sFv (Cancer Res., 52: 6413-6417, 1992). These previous studies indicated the potential utility of radioiodinated sFv and other Ig fragments for use in radioimmunoguided surgery with a hand-held probe, diagnostic imaging, and possibly therapy. The present study compares the distribution in normal tissues of the 4 Ig forms of monoclonal antibody (MAb) CC49, which is directed against a pancarcinoma antigen (tumor-associated glycoprotein-72). 125I-labeled sFv, Fab', F(ab')2, and IgG of MAb CC49 were administered to athymic mice either bearing or not bearing the tumor-associated glycoprotein-72 positive human colon carcinoma xenograft (LS-174T). At various intervals following the i.v. injection of the Ig forms, the liver, spleen, kidneys, and lungs were removed for autoradiographic analyses. Dramatic differences were observed in the kidney; the IgG was found only in the renal vasculature, whereas the Fab', F(ab')2, and sFv showed a high density of grains in the cortical tubules. In the liver, the IgG and F(ab')2 were found in association with hepatocytes, Kupffer cells, and in the sinusoids; the Fab' and sFv were primarily associated with the Kupffer cells. In the spleen, the Ig forms localized to the marginal zones surrounding the lymphoid follicles. No specific accumulation of grains for any of the Ig forms was observed in the lung. In each of the tissues, the clearance rates were related to the size of the Ig form. The localization in the liver and spleen was determined to be antigen-mediated.(ABSTRACT TRUNCATED AT 400 WORDS)
在先前的研究中，我们已将放射性碘化单链Fv（sFv）与其他免疫球蛋白（Ig）形式（完整IgG、F(ab')2和Fab'）的免疫化学特性、体内药代动力学及肿瘤穿透性进行了比较（《癌症研究》，51: 6363 - 6371, 1991）。生物分布研究表明，完整IgG和F(ab')2在肝脏和脾脏中的注射剂量/克百分比更高。Fab'和F(ab')2可观察到肾脏摄取，而sFv在这两个器官中均未显示出特异性定位。与其他Ig形式相比，125I标记的sFv在整个肿瘤异种移植中也表现出更均匀的分布（《癌症研究》，52: 3402 - 3408, 1992）。随后利用与放射性金属（177Lu）偶联的sFv进行的研究表明，sFv在肾脏中被代谢，与125I标记的sFv相比，177Lu标记的sFv获得了显著更高的注射剂量/克百分比（《癌症研究》，52: 6413 - 6417, 1992）。这些先前的研究表明，放射性碘化sFv和其他Ig片段在手持探头放射免疫导向手术、诊断成像以及可能的治疗中具有潜在用途。本研究比较了针对全癌抗原（肿瘤相关糖蛋白-72）的单克隆抗体（MAb）CC49的4种Ig形式在正常组织中的分布。将125I标记的MAb CC49的sFv、Fab'、F(ab')2和IgG给予患有或未患有肿瘤相关糖蛋白-72阳性人结肠癌异种移植（LS-174T）的无胸腺小鼠。在静脉注射Ig形式后的不同时间间隔，取出肝脏、脾脏、肾脏和肺进行放射自显影分析。在肾脏中观察到显著差异；IgG仅在肾血管中发现，而Fab'、F(ab')2和sFv在皮质小管中显示出高密度颗粒。在肝脏中，IgG和F(ab')2与肝细胞、库普弗细胞以及肝血窦相关；Fab'和sFv主要与库普弗细胞相关。在脾脏中，Ig形式定位于围绕淋巴滤泡的边缘区。在肺中未观察到任何一种Ig形式有颗粒的特异性聚集。在每个组织中，清除率与Ig形式的大小相关。确定在肝脏和脾脏中的定位是抗原介导的。（摘要截断于400字）
