Pallela V R, Rao S P, Thakur M L
Department of Radiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, USA.
J Nucl Med. 2000 Jun;41(6):1108-13.
A pretreatment with a single dose of an immunoconjugate (IC) that promises to enhance tumor uptake and decrease liver uptake of radiolabeled monoclonal antibodies (MAbs) might be of use in radioimmunodetection and radioimmunotherapy (RIT). We have shown previously that an interferon (IFN)-MAb (1:1) immunoconjugate (IC) enhances tumor uptake by a factor of 2 or more and reduces liver uptake by 50% in nude mice bearing human tumors. The aim of this study was to determine whether IFN modulates antigenic expression and to ascertain the most effective route of its administration, the optimal quantity to be administered, and the optimal duration of time to lapse between the administration of IC and the radiolabeled MAb.
IFN-alpha-2b and anticarcinoembryonic antigen-F6 (IgG2a) MAb were conjugated (1:1), and F(ab')2 of the MAb was labeled with 99mTc. Human colorectal tumors were grown in nude mice by implanting 5 x 10(6) LS174T confluent cells grown in culture. Mice, 5 in each group, received 20 x 10(3) IU intravenously, intramuscularly, or intraperitoneally and 40 x 10(3), 60 x 10(3), and 80 x 10(3) IU intravenously 30 min before the intravenous administration of 25.9 MBq 99mTc/20 microg F(ab')2. Mice in the control groups received 99mTc-F(ab')2 but not the conjugate. Twenty-four hours later mice were killed and imaged, and tissues were removed for quantitative (percentage injected dose/g [% ID/g]) distribution of 99mTc.
In all conjugate-receiving mice, the tumor uptake was higher and the liver uptake was lower (P < 0.01) than that in the control mice with the exception of liver uptake, which was not significantly different in mice receiving 80 x 10(3) IU conjugate. The optimal results were apparent in mice pretreated with 40 x 10(3) IU conjugate in which tumor uptake was enhanced by a factor of 2.3 (4.8 +/- 0.5 %ID/g versus 11 +/- 0.7 %ID/g; P < 0.01). The renal uptake remained unchanged, and the tumor-to-muscle ratios increased from 11.5 +/- 6.8 to 14.6 +/- 3.9, and the tumor-to-blood ratios increased from 4.4 +/- 1.8 to 8.3 +/- 2.4. The liver uptake decreased from 9.5% +/- 1% to 5% +/- 1.6%. Results were attributed to enhanced tumor blood flow, increased antigenic expression, and blocking of hepatic nonspecific Fc receptors.
A pretreatment with IFN-MAb conjugate is a worthwhile approach to consider in radioimmunoscintigraphy and RIT.
用单剂量免疫缀合物（IC）进行预处理有望增强放射性标记单克隆抗体（MAb）的肿瘤摄取并减少肝脏摄取，这可能在放射免疫检测和放射免疫治疗（RIT）中有用。我们之前已经表明，干扰素（IFN）-MAb（1:1）免疫缀合物（IC）可使荷人肿瘤裸鼠的肿瘤摄取提高2倍或更多，并使肝脏摄取降低50%。本研究的目的是确定IFN是否调节抗原表达，并确定其最有效的给药途径、最佳给药量以及IC给药与放射性标记MAb给药之间的最佳间隔时间。
将IFN-α-2b与抗癌胚抗原-F6（IgG2a）MAb（1:1）偶联，MAb的F(ab')2用99mTc标记。通过植入5×10(6)个培养的汇合LS174T细胞在裸鼠体内培育人结肠肿瘤。每组5只小鼠，在静脉注射25.9 MBq 99mTc/20 μg F(ab')2前30分钟，分别经静脉、肌肉或腹腔注射20×10(3) IU，以及经静脉注射40×10(3)、60×10(3)和80×10(3) IU。对照组小鼠接受99mTc-F(ab')2但不接受缀合物。24小时后处死小鼠并成像，取出组织进行99mTc的定量（注射剂量百分比/克 [% ID/g]）分布分析。
除接受80×10(3) IU缀合物的小鼠肝脏摄取无显著差异外，所有接受缀合物的小鼠的肿瘤摄取均高于对照组小鼠，肝脏摄取低于对照组小鼠（P < 0.01）。在用40×10(3) IU缀合物预处理的小鼠中观察到最佳结果，其中肿瘤摄取提高了2.3倍（4.8±0.5 %ID/g对11±0.7 %ID/g；P < 0.01）。肾脏摄取保持不变，肿瘤与肌肉的比值从11.5±6.8增加到14.6±3.9，肿瘤与血液的比值从4.4±1.8增加到8.3±2.4。肝脏摄取从9.5%±1%降至5%±1.6%。结果归因于肿瘤血流增加、抗原表达增加以及肝脏非特异性Fc受体的阻断。
在放射免疫闪烁显像和RIT中，用IFN-MAb缀合物进行预处理是一种值得考虑的方法。
