Feasibility of Affibody-Based Bioorthogonal Chemistry Mediated Radionuclide Pretargeting
Feasibility of Affibody-Based Bioorthogonal Chemistry Mediated Radionuclide Pretargeting
复制标题
DOI：
10.2967/jnumed.115.162248
复制
发表时间：
2016-03-01
影响因子：
9.3
通讯作者：
Tolmachev, Vladimir
中科院分区：
文献类型：
--
作者：
Altai, Mohamed;Perols, Anna;Tolmachev, Vladimir
亲和体分子是一类新型的放射性核素肿瘤靶向探针。亲和体分子的小尺寸有利于在肿瘤中的快速定位和从循环中清除。然而，亲和体分子的高肾重吸收阻止了残留放射性金属的使用，包括几种有前途的低能（β-和α-发射体）用于放射性核素治疗。我们测试了一个假设，即由反式环辛烯（TCO）和四嗪之间的生物正交相互作用介导的基于亲和体的预靶向在肿瘤异种移植物中比在肾脏中提供更高的放射性金属积累。方法：将TCO与抗人表皮生长因子受体2（HER 2）亲和体分子Z（2395）偶联。用In-111和Lu-177标记DOTA-四嗪。在表达HER 2的SKOV-3和BT474细胞系中研究了体外预靶向。对携带SKOV-3异种移植物的BALB/C nu/nu小鼠进行体内研究。结果：I-125-Z（2395）-TCO在体外以45 +/- 16 pM的亲和力特异性结合HER 2表达细胞。In-111-四嗪与Z（2325）-TCO预处理的细胞特异性结合。体内研究证明了HER 2特异性I-125-Z（2395）-TCO在异种移植物中的蓄积。当在注射Z（2395）-TCO后4小时注射放射性标记的示踪剂时，TCO介导的In-111-四嗪在肿瘤中定位。在注射后1小时，In-111-四嗪和Lu-177-四嗪的肿瘤摄取比肾摄取高约2倍。与直接靶向相比，预靶向使In-111的肾摄取减少了56倍以上。结论：证明了基于亲和体的生物正交化学介导的预靶向的可行性。预靶向的使用提供了肾中放射性金属积累的实质性减少，为姑息性放射性核素治疗创造了先决条件。
Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of Affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal reabsorption of Affibody molecules prevents the use of residualizing radiometals, including several promising low-energy (beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that Affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys. Methods: TCO was conjugated to the anti-human epidermal growth factor receptor 2 (HER2) Affibody molecule Z(2395). DOTA-tetrazine was labeled with In-111 and Lu-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts. Results: I-125-Z(2395)-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45 +/- 16 pM. In-111-tetrazine bound specifically and selectively to Z(2325)-TCO pretreated cells. In vivo studies demonstrated HER2-specific I-125-Z(2395)-TCO accumulation in xenografts. TCO-mediated In-111-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z(2395)-TCO. At 1 h after injection, the tumor uptake of In-111-tetrazine and Lu-177-tetrazine was approximately 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of In-111 in comparison with direct targeting. Conclusion: The feasibility of Affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pre-targeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.