使用体内212Pb/212Bi发生器对荷瘤小鼠进行预靶向放射免疫治疗。

Pretargeted radioimmunotherapy in tumored mice using an in vivo 212Pb/212Bi generator.

作者信息

Su Fu-Min, Beaumier Paul, Axworthy Don, Atcher Robert, Fritzberg Alan

机构信息

NeoRx Corp., Seattle, WA 98119, USA.

出版信息

Nucl Med Biol. 2005 Oct;32(7):741-7. doi: 10.1016/j.nucmedbio.2005.06.009.

DOI:10.1016/j.nucmedbio.2005.06.009

PMID:16243650

Abstract

OBJECTIVE

Pretargeting is the concept that combines optimal delivery of the antibody and rapid capture and elimination of the radioactivity. In this study, we evaluated the potential of antibody pretargeting to enable the tumor-targeting (212)Pb for in vivo generation of (212)Bi for alpha particle radiotherapy.

METHODS

The (212)Pb/(212)Bi chelate of DOTA-biotin, as well as their gamma-emitting analogues, (203)Pb and (205)Bi, was prepared and characterized. The radiolabeled compounds were injected in animals for evaluation of tumor targeting and normal tissue uptake and retention. In the pretargeting protocol, injection of 400 microg of NR-LU-10 antibody-streptavidin conjugate was given at t = 0 h, then 100 microg of N-acetyl-galatosamine-biotin clearing agent was injected at t = 20-24 h; finally, 1 microg of (212)Pb/(212)Bi-DOTA-biotin was injected 6 h later.

RESULTS

Both (203)Pb and (205)Bi-DOTA-biotin were stable for at least 4 days in the different challenging solutions including PBS, 10 mM DTPA and serum. Contrary to its gamma-emitting analogues, radiolabeled (212)Pb-DOTA-biotin was not stable. There was greater than 30% of free (212)Bi released 4 h after (212)Pb-labeled DOTA-biotin. The results of pretargeting protocol of (203)Pb and (205)Bi-DOTA-biotin showed that the tumor target reached 20% injected dose (ID)/g at 4 h postinjection and remained high for 5 days. The %ID/g in the whole blood and other nontarget organs was low after administration of labeled (203)Pb and (205)Bi-DOTA-biotin similar to the biodistribution of labeled DOTA-biotin alone. In the animals administered (212)Pb-DOTA-biotin, radioactivity in nontarget organs was low except the kidneys. The %ID/g in the kidney for (212)Bi was 14.5 at 2 h, higher than (212)Pb, but dropped to about 6% ID/g by 4 h. However, tumor uptake for (212)Pb and (212)Bi was >25% ID/g at 1 h postinjection and remained so through 24 h.

CONCLUSIONS

Antibody pretargeting system with Mab-streptavidin, clearing agent and DOTA-biotin provides the potential of (212)Bi for solid tumor radiotherapy despite the release of (212)Bi after (212)Pb decay. Dosimetry calculations resulted in tumor dose at 93 rad/muCi and ratios of tumor to marrow and kidney at 386:1 and 12:1, respectively.

摘要

目的

预靶向是一种将抗体的最佳递送与放射性的快速捕获和清除相结合的概念。在本研究中，我们评估了抗体预靶向使肿瘤靶向（212）Pb以在体内生成用于α粒子放射治疗的（212）Bi的潜力。

方法

制备并表征了DOTA - 生物素的（212）Pb/（212）Bi螯合物及其γ发射类似物（203）Pb和（205）Bi。将放射性标记的化合物注射到动物体内，以评估肿瘤靶向性以及正常组织的摄取和滞留情况。在预靶向方案中，在t = 0 h时注射400 μg的NR - LU - 10抗体 - 链霉亲和素缀合物，然后在t = 20 - 24 h时注射100 μg的N - 乙酰 - 半乳糖胺 - 生物素清除剂；最后，6小时后注射1 μg的（212）Pb/（212）Bi - DOTA - 生物素。

结果

（203）Pb和（205）Bi - DOTA - 生物素在包括PBS、10 mM DTPA和血清在内的不同挑战性溶液中至少稳定4天。与其γ发射类似物相反，放射性标记的（212）Pb - DOTA - 生物素不稳定。（212）Pb标记的DOTA - 生物素4小时后释放出超过30%的游离（212）Bi。（203）Pb和（205）Bi - DOTA - 生物素预靶向方案的结果表明，注射后4小时肿瘤靶向率达到20%注射剂量（ID）/g，并在5天内保持较高水平。给予标记的（203）Pb和（205）Bi - DOTA - 生物素后，全血和其他非靶器官中的%ID/g较低，类似于单独标记的DOTA - 生物素的生物分布。在给予（212）Pb - DOTA - 生物素的动物中，除肾脏外非靶器官中的放射性较低。（212）Bi在肾脏中的%ID/g在2小时时为14.5，高于（212）Pb，但到4小时时降至约6% ID/g。然而，（212）Pb和（212）Bi的肿瘤摄取在注射后1小时时>25% ID/g，并在24小时内保持如此。