177镥和90钇在小鼠淋巴瘤异种移植模型中进行抗CD20预靶向放射免疫治疗的疗效比较
Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models.
作者信息
Frost Sofia H L, Frayo Shani L, Miller Brian W, Orozco Johnnie J, Booth Garrett C, Hylarides Mark D, Lin Yukang, Green Damian J, Gopal Ajay K, Pagel John M, Bäck Tom A, Fisher Darrell R, Press Oliver W
机构信息
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
Pacific Northwest National Laboratory, Richland, WA, United States of America; College of Optical Sciences, The University of Arizona, Tucson, AZ, United States of America.
出版信息
PLoS One. 2015 Mar 18;10(3):e0120561. doi: 10.1371/journal.pone.0120561. eCollection 2015.
PURPOSE
Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.
METHODS
Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent.
RESULTS
The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTA-biotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes.
CONCLUSION
90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in these human lymphoma xenograft models.
目的
预靶向放射免疫疗法（PRIT）是一种多步骤方法，可将高剂量放疗选择性地递送至肿瘤细胞，同时使周围组织的暴露最小化。钇-90（90Y）和镥-177（177Lu）是用于放射免疫疗法的两种最有前景的发射β粒子的放射性核素，尽管它们具有相似的化学性质，但在放射物理特征方面有明显差异。这些差异可能对肿瘤和正常器官的吸收剂量产生重要影响。虽然90Y已成功应用于许多临床前和临床放射免疫疗法中，但很少有关于177Lu的预靶向研究发表。因此，我们比较了将90Y或177Lu靶向小鼠人B细胞淋巴瘤异种移植瘤的治疗潜力。
方法
在携带Ramos（伯基特淋巴瘤）或Granta（套细胞淋巴瘤）异种移植瘤的雌性无胸腺裸鼠中进行平行实验，评估生物分布、成像、剂量测定、治疗效果和毒性，使用抗CD20抗体-链霉亲和素偶联物（1F5-SA）和90Y或177Lu标记的1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-生物素第二步试剂。
结果
两种放射性核素在肿瘤和正常器官中的生物分布相当；然而，90Y（1.3 Gy/MBq）递送至肿瘤的吸收辐射剂量是177Lu（0.6 Gy/MBq）的两倍多。更重要的是，90Y-DOTA-生物素治疗比177Lu-DOTA-生物素显著更有效，用37 MBq 90Y可使100%携带Ramos异种移植瘤的小鼠治愈，而使用相同量的177Lu-DOTA-生物素则无小鼠治愈。在携带Granta异种移植瘤的小鼠中也观察到类似结果，90Y-PRIT使80%的小鼠治愈，177Lu-PRIT则无小鼠治愈。两种同位素的毒性相当。
结论
在这些人淋巴瘤异种移植模型中，对于链霉亲和素-生物素PRIT方法，90Y在治疗上优于177Lu。
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