Dosimetric evaluation and radioimmunotherapy of anti-tumour multivalent Fab' fragments
Dosimetric evaluation and radioimmunotherapy of anti-tumour multivalent Fab' fragments
复制标题
DOI：
10.1038/sj.bjc.6690795
复制
发表时间：
1999-11-01
影响因子：
8.8
通讯作者：
Begent, RHJ
中科院分区：
文献类型：
--
作者：
Casey, JL;Pedley, RB;Begent, RHJ
我们一直在研究使用交联二价（DFM）和三价（TFM）版本的抗癌胚抗原（CEA）单克隆抗体A5B7作为亲本形式（IgG和F(ab)）的可能替代品(2)，这些形式先前已用于结直肠癌的临床放射免疫治疗（RIT）研究，类似大小的DFM和F（ab）的比较生物分布研究，以及TFM和IgG。（131）I和（90）Y的放射性标记先前已在人类结直肠癌LS174T裸鼠异种移植模型中被描述（Casey et al . (1996) Br J Cancer 74: 1397-1405）。在本研究中，对异种移植模型中辐射分布和RIT的定量估计为选择最合适的RIT组合提供了更多的见解。当抗体被标记为（90）Y时，所有组织中的辐射剂量都明显更高。主要贡献器官是肾脏、肝脏和脾脏。注射（90）y标记的DFM和F(ab')(2)对肾脏的吸收剂量极高，由于放射性金属的积累会导致极高的毒性。这些组合显然不适合RIT， （90）Y-TFM对肾脏的累积剂量比二价形式低3倍，但仍然是（90）Y-IgG的两倍。TFM比IgG更快地从血液中清除，产生更高的肿瘤与血液比率。因此，当仅考虑肿瘤与血液的比例或总吸收剂量时，数据表明TFM将是最合适的候选者。然而，当校正等量血水平时，正常组织的TFM剂量约为IgG水平的两倍，使整个肿瘤与正常组织的比例增加了两倍。此外，RIT显示，在相同的毒性水平和一半的给药活性下，（90）Y-IgG产生了更大的治疗反应。这表明与放射性核素（90）Y结合的最有希望的A5B7抗体形式可能是IgG。剂量学分析显示，所有（131）i标记抗体的肿瘤与正常组织的比例都更高。这表明（131）I可能是一种更适合RIT的放射性核素，因为它对正常组织的毒性较低。（131） i标记的DFM可能是抗A5B7抗体和放射性核素的最佳组合，其血药比和正常组织比在等量孵育水平下最高。剂量学估计与RIT结果一致，必须给予（131）I-DFM活性的两倍才能产生与（131）I-TFM相似的治疗效果。该治疗实验的毒性很小，需要在更高剂量下进行进一步的实验，以观察更高的初始剂量率是否会对（131）I-DFM有任何好处。(C) 1999年癌症研究运动。
We have been investigating the use of cross-linked divalent (DFM) and trivalent (TFM) versions of the anti-carcinoembryonic antigen (CEA) monoclonal antibody A5B7 as possible alternatives to the parent forms (IgG and F(ab')(2)) which have been used previously in clinical radioimmunotherapy (RIT) studies in colorectal carcinoma, Comparative biodistribution studies of similar sized DFM and F(ab), and TFM and IgG, radiolabeled with both (131)I and (90)Y have been described previously using the human colorectal tumour LS174T nude mouse xenograft model (Casey et al (1996) Br J Cancer 74: 1397-1405). in this study quantitative estimates of radiation distribution and RIT in the xenograft model provided more insight into selecting the most suitable combination for future RIT. Radiation doses were significantly higher in all tissues when antibodies were labelled with (90)Y. Major contributing organs were the kidneys, liver and spleen, The extremely high absorbed dose to the kidneys on injection of (90)Y-labelled DFM and F(ab')(2), as a result of accumulation of the radiometal would result in extremely high toxicity. These combinations are clearly unsuitable for RIT, Cumulative dose of (90)Y-TFM to the kidney was 3 times lower than the divalent forms but still twice as high as for (90)Y-IgG. TFM clears faster from the blood than IgG, producing higher tumour to blood ratios. Therefore when considering only the tumour to blood ratios or the total absorbed dose, the data suggests that TFM would be the most suitable candidate. However, when corrected for equitoxic blood levels, doses to normal tissues for TFM were approximately twice the level of IgG, producing a two-fold increase in the overall tumour to normal tissue ratio. In addition RIT revealed that for a similar level of toxicity and half the administered activity, (90)Y-IgG produced a greater therapeutic response. This suggests that the most promising A5B7 antibody form with the radionuclide (90)Y may be IgG. Dosimetry analysis revealed that the tumour to normal tissue ratios were greater for all (131)I-labelled antibodies. This suggests that (131)I may be a more suitable radionuclide for RIT, in terms of lower toxicity to normal tissues. The highest tumour to blood dose and tumour to normal tissue ratio at equitoxic brood levels was (131)I-labelled DFM, suggesting that (131)I-DFM may be best combination of antibody and radionuclide for A5B7. The dosimetry estimates were in agreement with RIT results in that twice the activity of (131)I-DFM must be administered to produce a similar therapeutic effect as (131)I-TFM. The toxicity in this therapy experiment was minimal and further experiments at higher doses are required to observe if there would be any advantage of a higher initial dose rate for (131)I-DFM. (C) 1999 Cancer Research Campaign.