Therapeutic advantages of Auger electron- over β-emitting radiometals or radioiodine when conjugated to internalizing antibodies
Therapeutic advantages of Auger electron- over β-emitting radiometals or radioiodine when conjugated to internalizing antibodies
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DOI：
10.1007/s002590000272
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发表时间：
2000-07-01
期刊：
影响因子：
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通讯作者：
Becker, W
中科院分区：
文献类型：
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作者：
Behr, TM;Béhé, M;Becker, W
最近的研究表明，与β-发射体相比，当用俄歇电子发射体标记时，内化单克隆抗体（MAb）的抗肿瘤功效更高。本研究的目的是在结肠癌模型中比较用俄歇电子发射体（I-125，In-111）标记的内化单克隆抗体CO 17 -1A与常规β（-）-发射体（I-131，Y-90）的抗肿瘤功效和毒性，并评估残留放射性金属是否可能具有优于常规碘化缀合物的治疗优势。在皮下移植人结肠癌的裸鼠中进行了I-125-、In-111-或Y-88-标记的CO 17 -1A的生物分布研究。为了治疗，给小鼠注射未标记的或I-125-、I-131-、In-111-或Y-90-标记的CO 17 -1A IgG（2a），而对照组不接受治疗或给予放射性标记的同种型匹配的无关抗体。通过将结果与用抗癌胚抗原（CEA）抗体获得的结果进行比较来评估内化的影响，所述抗癌胚抗原（CEA）抗体不内化至相关程度。测定每种药物的最大耐受活性（MTA）和剂量（MTD）。监测骨髓毒性和潜在的第二器官毒性以及肿瘤生长。进行骨髓移植（BMT）以实现剂量强化。放射性金属显示出比相应的碘化缀合物显著更好的肿瘤-血液比率。没有人工载体的I-131-和I-125-CO 17 -1A的MTA分别为11.1 MBq（300 μ Ci）和111 MBq（3 mCi）; Y-90-的金属MTA达到4 MBq（100 μ Ci），In-111-CO 17 -1A的金属MTA达到85 MBq（2.3 mCi）。在所有病例中，骨髓毒性均为剂量限制性。BMT使I-131标记的CO 17-IA的MTA增加至15 MBq（400 μ Ci），Y-90标记的CO 17-IA的MTA增加至4.4 MBq（120 μ Ci），In-111标记的CO 17 -1A的MTA增加至118 MBq（3.2 mCi），而I-125-CO 17 -1A的MTA未达到185 MBq（5 mCi）。虽然未标记的CO 17 -1A没有显著的治疗效果，但其放射性标记形式显著延缓了肿瘤生长。治疗结果有显著性差异（P
Recent studies suggest a higher anti-tumour efficacy of internalizing monoclonal antibodies (MAbs) when labelled with Auger electron emitters, as compared with beta-emitters. The aim of this study was to compare the anti-tumour efficacy and toxicity of the internalizing MAb, CO17-1A, labelled with Auger electron emitters (I-125, In-111) versus conventional beta(-)-emitters (I-131, Y-90) in a colon cancer model, and to assess whether the residualizing radiometals may have therapeutic advantages over the conventionally iodinated conjugates. Biodistribution studies of I-125-, In-111- or Y-88-labelled CO17-1A were performed in nude mice bearing subcutaneous human colon cancer xenografts. For therapy, the mice were injected with either unlabelled or I-125-, I-131-, In-111- or Y-90-labelled CO17-1A IgG(2a), whereas control groups were left untreated or were given a radiolabelled isotype-matched irrelevant antibody. The influence of internalization was assessed by comparing the results with those obtained with an anti-carcinoembryonic antigen (CEA) antibody which does not internalize to a relevant extent. The maximum tolerated activities (MTA) and doses (MTD) of each agent were determined. Myelotoxicity and potential second-organ toxicities, as well as tumour growth, were monitored. Bone marrow transplantation (BMT) was performed in order to enable dose intensification. Radiometals showed significantly better tumour-to-blood ratios than the respective iodinated conjugates. The MTAs of I-131- and I-125-CO17-1A without artificial support were 11.1 MBq (300 mu Ci) and 111 MBq (3 mCi), respectively; the MTA of the metals was reached at 4 MBq (100 mu Ci) for Y-90-, and at 85 MBq (2.3 mCi) for In-111-CO17-1A. Myelotoxicity was dose limiting in all cases. BMT enabled an increase in the MTA to 15 MBq (400 mu Ci) of I-131-labelled CO17-IA, to 4.4 MBq (120 mu Ci) of Y-90-labelled CO17-IA, and to 118 MBq (3.2 mCi) of In-111-labelled CO17-1A, while the MTA of I-125-CO17-1A had not been reached at 185 MBq (5 mCi) with BMT. Whereas no significant therapeutic effects were seen with unlabelled CO17-1A, tumour growth was retarded significantly with its radiolabelled forms. The therapeutic results were significantly (P