Casey J L, King D J, Pedley R B, Boden J A, Boden R, Chaplin L C, Dorning M, Begent R H
Department of Clinical Oncology, Royal Free Hospital School of Medicine, London, UK.
Br J Cancer. 1998 Nov;78(10):1307-12. doi: 10.1038/bjc.1998.676.
Radioimmunotherapy (RIT) is currently limited by toxicity to normal tissues as a result of prolonged circulating radioantibody in the blood. In this study, the use of a clearing antibody was investigated (second antibody) in an attempt to reduce blood background levels of [90Y]A5B7 immunoglobulin G (IgG) activity, and, therefore, improve the therapeutic tumour-blood ratio in nude mice bearing human colorectal tumour xenografts. The second antibody was raised against the 12N4 macrocycle group used for chelation of 90Y, and is, thus, applicable to any anti-tumour antibody labelled with this methodology. Second antibody was administered 18, 24 or 48 h after radiolabelled antibody injection and produced up to a tenfold reduction in blood levels and a tenfold improvement in tumour-blood ratios. This has the advantage of reducing the risk of myelotoxicity caused by prolonged retention of activity in the blood. For all normal tissues, there was a similar or slightly lower uptake of [90Y]IgG with second antibody clearance, apart from a transient rise in liver activity due to complexes of primary and secondary antibody clearing via the liver. As a result of clearance of [90Y]IgG from the blood pool, there was an associated fall in the amount of antibody at the tumour site (up to 3.3-fold) at later time points for mice injected with second antibody. However, despite this, tumour-blood ratios remained superior to the control group at these later time points. Estimated dosimetry evaluation revealed that total dose to normal tissues, blood and tumour was lower than for the non-clearance group. Surprisingly, however, there was little improvement in total estimated tumour-blood dose ratio over the time period studied. This was probably because the majority of the dose was delivered to both the blood and tumour within the first 24 h after administration of [90Y]IgG, so that giving the clearing agent after this time did not produce a large difference in total estimated dose. The anti-macrocycle second antibody proved to be a successful clearing agent and could potentially be applied to any anti-tumour antibody coupled with the 12N4 macrocycle. In the light of the estimated dosimetry results described here, it would probably be most useful given at earlier time points (i.e. before 18 h after injection of primary antibody) to produce an improved tumour-blood ratio of total dose. Development of this strategy may allow higher levels of activity to be administered for RIT, and repeated dosing regimens.
放射免疫疗法（RIT）目前受到限制，因为血液中放射性抗体的循环时间延长会对正常组织产生毒性。在本研究中，研究了使用清除抗体（第二抗体）以试图降低[90Y]A5B7免疫球蛋白G（IgG）活性的血液本底水平，从而提高荷人结直肠癌异种移植瘤裸鼠的治疗性肿瘤-血液比。第二抗体是针对用于螯合90Y的12N4大环基团产生的，因此适用于任何用该方法标记的抗肿瘤抗体。在注射放射性标记抗体后18、24或48小时给予第二抗体，可使血液水平降低多达10倍，肿瘤-血液比提高10倍。这具有降低因血液中活性物质长期滞留而导致骨髓毒性风险的优点。对于所有正常组织，除了由于初级和次级抗体复合物通过肝脏清除导致肝脏活性短暂升高外，第二抗体清除后[90Y]IgG的摄取相似或略低。由于从血池清除[90Y]IgG，在注射第二抗体的小鼠的较晚时间点，肿瘤部位的抗体量相应下降（高达3.3倍）。然而，尽管如此，在这些较晚时间点，肿瘤-血液比仍优于对照组。估计剂量学评估显示，正常组织、血液和肿瘤的总剂量低于未清除组。然而，令人惊讶的是，在所研究的时间段内，总估计肿瘤-血液剂量比几乎没有改善。这可能是因为大部分剂量在给予[90Y]IgG后的头24小时内就输送到了血液和肿瘤中，因此在此时间之后给予清除剂在总估计剂量上没有产生很大差异。抗大环第二抗体被证明是一种成功的清除剂，并且可能适用于与12N4大环偶联的任何抗肿瘤抗体。根据此处描述的估计剂量学结果，在较早时间点（即注射初级抗体后18小时之前）给予可能最有用，以提高总剂量的肿瘤-血液比。该策略的发展可能允许在RIT中给予更高水平的活性物质，并采用重复给药方案。
