Beatty B G, O'Conner-Tressel M, Do T, Paxton R J, Beatty J D
City of Hope National Medical Center, Department of General and Oncology Surgery, Durarte, California 91010.
Cancer Res. 1990 Feb 1;50(3 Suppl):846s-851s.
The purpose of this study was to examine the mechanism of specific antibody pretreatment for reduction of liver uptake of 111In-labeled monoclonal antibody (MAB). Previous work with an anti-carcinoembryonic antigen (CEA) MAB (T84.66) and LS174T human colon cancer xenografts in nude mice has shown that giving a high dose (0.2 mg) of unlabeled T84.66 in conjunction with the same MAB (T84.66) labeled with 111In (Indacea) significantly lowered the liver uptake of 111In. High performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were used to assess the radiolabeled components in serum and liver at different times following administration of Indacea in normal and tumor bearing mice. In serum the 111In remained associated with the IgG in both tumor bearing and non-tumor bearing mice. Liver uptake of 111In in mice without tumor was low (8-12% injected dose/g) and both IgG and a low molecular weight metabolite were found in the liver homogenates. Liver uptake in tumor bearing mice increased dramatically (15-40% injected dose/g) with size of tumor and in addition to the IgG and low molecular weight components, a high molecular weight compound was identified. Administration of CEA: Indacea complexes to non-tumor bearing mice produced the same high pressure liquid chromatography and gel patterns as those seen in mice with large (greater than 1 g) tumors. Liver homogenates from tumor bearing mice given specific antibody pretreatment showed the same patterns seen with non-tumor bearing mice (no high molecular weight peak). In conclusion, CEA:Indacea complexes are formed in tumor bearing mice and rapidly cleared by the liver. Specific antibody pretreatment results in the production of unlabeled CEA:MAB complexes causing a reduction in the formation of CEA:Indacea complexes and a lower liver uptake of 111In.
本研究的目的是探讨特异性抗体预处理降低¹¹¹铟标记单克隆抗体（MAB）肝脏摄取的机制。先前对裸鼠体内抗癌胚抗原（CEA）单克隆抗体（T84.66）和LS174T人结肠癌异种移植瘤的研究表明，给予高剂量（0.2mg）未标记的T84.66并联合¹¹¹铟标记的相同单克隆抗体（Indacea），可显著降低¹¹¹铟的肝脏摄取。采用高效液相色谱法和十二烷基硫酸钠-聚丙烯酰胺凝胶电泳法，评估正常小鼠和荷瘤小鼠给予Indacea后不同时间血清和肝脏中的放射性标记成分。在血清中，¹¹¹铟在荷瘤小鼠和非荷瘤小鼠体内均与IgG结合。无肿瘤小鼠肝脏对¹¹¹铟的摄取较低（8-12%注射剂量/g），肝脏匀浆中可发现IgG和一种低分子量代谢产物。荷瘤小鼠肝脏对¹¹¹铟的摄取随肿瘤大小显著增加（15-40%注射剂量/g），除了IgG和低分子量成分外，还鉴定出一种高分子量化合物。向非荷瘤小鼠注射CEA:Indacea复合物，产生的高效液相色谱和凝胶图谱与大肿瘤（大于1g）小鼠相同。给予特异性抗体预处理的荷瘤小鼠肝脏匀浆显示出与非荷瘤小鼠相同的图谱（无高分子量峰）。总之，荷瘤小鼠体内形成CEA:Indacea复合物并迅速被肝脏清除。特异性抗体预处理导致未标记的CEA:MAB复合物生成，从而减少CEA:Indacea复合物的形成，降低¹¹¹铟的肝脏摄取。
