Bz-DOTA 和 CHX-A''-DTPA 对 ABD 融合型抗 HER2 Affibody 分子的生物分布的影响：对（114m）In 介导的靶向治疗的意义。
The influence of Bz-DOTA and CHX-A''-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules: implications for (114m)In-mediated targeting therapy.
机构信息
Affibody AB, Bromma, Sweden.
出版信息
Eur J Nucl Med Mol Imaging. 2009 Sep;36(9):1460-8. doi: 10.1007/s00259-009-1134-9. Epub 2009 May 9.
PURPOSE
Affibody molecules represent a novel class of high-affinity agents for radionuclide tumour targeting. Fusion of the Affibody molecules with an albumin-binding domain (ABD) enables modification of the blood kinetics of the Affibody molecules and reduction of the renal dose. (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2), an anti-HER2 Affibody molecule-ABD fusion protein has earlier demonstrated promising results in treatment of HER2-expressing micro-xenografts in mice. The use of the in vivo generator (114m)In/(114)In as a label for ABD-fused Affibody molecules would create preconditions for efficient treatment of both micrometastases (due to conversion and Auger electrons of (114m)In) and bulky tumours (due to high-energy beta particles from the daughter nuclide (114)In). The goal of this study was to investigate if different chelators influence the biodistribution of ABD-(Z(HER2:342))(2) and to find an optimal chelator for attachment of (114m)In to the Affibody molecule-ABD fusion protein.
METHODS
Isothiocyanate derivatives of Bz-DOTA and CHX-A''-DTPA were coupled to ABD-(Z(HER2:342))(2). The cellular processing of both conjugates was studied in vitro. The influence of chelators on the biodistribution was investigated in mice using double isotope ((114m)In and (111)In) labelling.
RESULTS
The apparent affinity of CHX-A''-DTPA-ABD-(Z(HER2:342))(2) and Bz-DOTA-ABD-(Z(HER2:342))(2) to the extracellular domain of HER2 was similar, 13.5 and 15.0 pM, respectively. It was found that both conjugates were internalized by SKOV-3 cells. The use of CHX-A''-DTPA provided better cellular retention of the radioactivity, better tumour accumulation of radioactivity and better tumour to organ dose ratios than Bz-DOTA-ABD-(Z(HER2:342))(2).
CONCLUSION
CHX-A''-DTPA is more suitable for (114m)In labelling of Affibody molecule-ABD fusion proteins for radionuclide therapy.
目的
亲和体分子是一类新型的高亲和力放射性核素肿瘤靶向试剂。将亲和体分子与白蛋白结合域（ABD）融合，可改变亲和体分子的血液动力学特性，并降低肾脏剂量。（177）Lu-CHX-A''-DTPA-ABD-（Z（HER2：342））（2）是一种抗 HER2 的亲和体分子-ABD 融合蛋白，之前在治疗荷 HER2 微移植瘤的小鼠模型中显示出良好的疗效。使用体内发生器（114m）In/（114）In 作为 ABD 融合亲和体分子的标记物，将为有效治疗微转移灶（由于（114m）In 的转化和俄歇电子）和大肿瘤（由于子核素（114）In 的高能β粒子）创造条件。本研究的目的是研究不同螯合剂是否会影响 ABD-（Z（HER2：342））（2）的生物分布，并找到与亲和体分子-ABD 融合蛋白结合的最佳螯合剂。
方法
将 Bz-DOTA 和 CHX-A''-DTPA 的异硫氰酸酯衍生物与 ABD-（Z（HER2：342））（2）偶联。在体外研究了两种缀合物的细胞处理过程。使用双同位素（（114m）In 和（111）In）标记法研究了螯合剂对生物分布的影响。
结果
CHX-A''-DTPA-ABD-（Z（HER2：342））（2）和 Bz-DOTA-ABD-（Z（HER2：342））（2）与 HER2 细胞外结构域的表观亲和力相似，分别为 13.5 和 15.0 pM。结果发现两种缀合物均被 SKOV-3 细胞内化。与 Bz-DOTA-ABD-（Z（HER2：342））（2）相比，CHX-A''-DTPA 可提供更好的细胞内放射性滞留、更好的肿瘤放射性积累和更好的肿瘤/器官剂量比。
结论
CHX-A''-DTPA 更适合用于（114m）In 标记亲和体分子-ABD 融合蛋白进行放射性核素治疗。
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