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首页> 外文期刊>The Journal of Nuclear Medicine >Site-specific radiometal labeling and improved biodistribution using ABY-027, a novel HER2-targeting affibody molecule-albumin-binding domain fusion protein
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Site-specific radiometal labeling and improved biodistribution using ABY-027, a novel HER2-targeting affibody molecule-albumin-binding domain fusion protein

机译：使用新型HER2靶向亲和分子-白蛋白结合域融合蛋白ABY-027进行位点特异性放射性金属标记并改善生物分布

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摘要

Because of their better penetration, smaller targeting proteins may be superior to antibodies for radioimmunotherapy of solid tumors. Therefore, Affibody molecules (6.5 kDa) have a potential for being suitable as targeted moiety for radiolabeled therapeutic proteins. Previous studies have demonstrated that a fusion of an Affibody molecule with an albumin-binding domain (ABD) provides a strong noncovalent binding to albumin in vivo. This strong noncovalent binding can be used for reduction of the renal uptake of the Affibody molecule while maintaining a size smaller than that of an antibody, which is important when using residualizing radionuclide labels conjugated to Affibody molecules. The goal of this study was to design and evaluate a new targeting Affibody - ABD fusion protein with improved biodistribution properties for radionuclide therapy. Methods: A novel Affibody-based construct, Z HER2:2891-ABD035-DOTA (ABY-027), was created by fusion of the reengineered HER2-binding Affibody molecule ZHER2:2891 to the N terminus of the high-affinity ABD035, and a maleimido-derivative of DOTA was conjugated at the C terminus of the construct. Binding and processing of 177Lu-ABY-027 by HER2-expressing cells were evaluated in vitro. Targeting of HER2-expressing SKOV-3 xenografts was evaluated in BALB/C nuu mice and compared with targeting of previously reported ABD-(Z HER2:342)2. Results: The binding affinity (dissociation constant) of ABY-027 to HER2 (74 pM) was the same as for the parental Z HER2:2891 (76 pM). ABY-027 was stably labeled with 177Lu and 111In with preserved specific binding to HER2-expressing cells in vitro. In vivo receptor saturation experiments demonstrated that targeting of SKOV-3 xenografts in BALB/C nuu mice was HER2-specific. 177Lu-ABY- 027 demonstrated substantially (2- to 3-fold) lower renal and hepatic uptake than previously assessed HER2-specific Affibody-based albumin-binding agents. Tumor uptake of radiolabeled ABY-027 at 48 h after injection was 2-fold higher than that for previously reported ABD-(ZHER2:342)2. Conclusion: An optimized molecular design of an ABD fusion protein resulted in an Affibody molecule construct with better properties for therapy. Fully preserved in vivo targeting of the fusion protein was shown in xenografted mice. Site-specific coupling of DOTA provides a uniform conjugate and creates the potential for labeling with a broad range of therapeutic radionuclides. The biodistribution of 177Lu-ABY-027 in a murine model suggests it is more suitable for therapy than alternative approaches.
机译：由于其更好的渗透性，较小的靶向蛋白可能优于实体瘤放射免疫疗法的抗体。因此，Affibody分子（6.5 kDa）有潜力适合用作放射性标记的治疗性蛋白质的靶向部分。先前的研究表明，Affibody分子与白蛋白结合域（ABD）的融合在体内提供了与白蛋白的强非共价结合。这种强的非共价结合可用于减少Affibody分子的肾脏摄取，同时保持小于抗体的大小，这在使用与Affibody分子缀合的残留放射性核素标记时很重要。这项研究的目的是设计和评估一种新的靶向Affibody-具有改善的生物分布特性的ABD融合蛋白，用于放射性核素治疗。方法：通过将重新设计的HER2结合Affibody分子ZHER2：2891与高亲和力ABD035的N末端融合，创建了一个基于Affibody的新型构建体Z HER2：2891-ABD035-DOTA（ABY-027），并且DOTA的马来酰亚胺衍生物被缀合在构建体的C末端。在体外评估了表达HER2的细胞对177Lu-ABY-027的结合和加工。在BALB / C nu / nu小鼠中评估了表达HER2的SKOV-3异种移植物的靶向性，并将其与先前报道的ABD-（Z HER2：342）2靶向性进行了比较。结果：ABY-027与HER2（74 pM）的结合亲和力（解离常数）与亲本Z HER2：2891（76 pM）相同。 ABY-027被177Lu和111In稳定标记，并在体外与表达HER2的细胞保持特异性结合。体内受体饱和实验表明，在BALB / C nu / nu小鼠中靶向SKOV-3异种移植物是HER2特异性的。 177Lu-ABY-027与先前评估的基于HER2的基于Affibody的白蛋白结合剂相比，肾和肝的摄取量低（2-3倍）。注射后48 h，放射性标记的ABY-027的肿瘤摄取比以前报道的ABD-（ZHER2：342）2高2倍。结论：ABD融合蛋白的优化分子设计产生了具有更好治疗特性的Affibody分子构建体。在异种移植的小鼠中显示了融合蛋白的完全保留的体内靶向。 DOTA的位点特异性偶联提供了均匀的结合物，并为广泛的治疗性放射性核素标记创造了潜力。 177Lu-ABY-027在鼠模型中的生物分布表明，它比其他方法更适合治疗。

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