[44Sc]Sc-CHX-A″-DTPA-RCCB6: A PET Tracer for Imaging CD70 Expression Across Latency Types of Burkitt Lymphoma

Xiaoyan Li, Yajie Zhao, Jessica C. Hsu, Eduardo A. Sarduy, Todd E. Barnhart, Jonathan W. Engle, Weijun Wei, Shuo Hu, Weibo Cai
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Abstract

CD70 is a promising target for advancing the diagnosis and treatment of Burkitt lymphoma (BL). A 44Sc-labeled single-domain antibody fragment tracer, [44Sc]Sc-CHX-A″-DTPA-RCCB6, was developed and assessed for its potential in CD70-targeted immuno-PET imaging using BL models. Methods: RCCB6 single-domain antibody was conjugated with CHX-A″-DTPA and radiolabeled with 44Sc. The final tracer, [44Sc]Sc-CHX-A″-DTPA-RCCB6, was assessed for stability both in vitro and in vivo. Cellular uptake, binding, and internalization assays were conducted using type III and type I latency BL cell lines to confirm the tracer’s specificity for CD70. Immuno-PET and biodistribution studies were performed in type III and type I latency BL models, whereas near-infrared fluorescence imaging was used to validate tumor accumulation. Finally, immunohistochemistry analysis was conducted on tumor tissues from both latency types to correlate between tracer accumulation and CD70 expression. Results: Radiolabeling of CHX-A″-DTPA-RCCB6 with 44Sc achieved high radiochemical yield and specific activity. The tracer was highly stable both in vitro and in vivo. In vitro cellular uptake and internalization assays confirmed the specific binding of [44Sc]Sc-CHX-A″-DTPA-RCCB6 to CD70 in type III latency BL cells. An inhibitory concentration of 50% of 16.45 ± 2.82 nM for RCCB6 and 38.74 ± 4.66 nM for CHX-A″-RCCB6 was determined from competition binding studies. Saturation binding studies determined the maximum number of binding sites, the association constant, and receptor density values for [44Sc]Sc-CHX-A″-DTPA-RCCB6 in type III latency BL cells to be 4.83 ± 0.52 pM, 19.75 ± 5.97 nM, and (2.36 ± 0.26) × 106 receptors per cell, respectively. Immuno-PET imaging and ex vivo biodistribution revealed high tracer accumulation in type III latency BL tumors, with sustained retention up to 6 h after injection (2.85 ± 0.84 %ID/g). Tracer uptake was minimal in both the blocked group and in type I latency BL tumors, with values of 0.35 ± 0.03 %ID/g and 0.58 ± 0.16 %ID/g, respectively. Near-infrared fluorescence imaging further confirmed tracer accumulation in type III latency BL tumors. Immunohistochemistry analysis supported these results, showing more intense CD70 staining in type III latency BL tumors compared with type I latency BL tumors. Conclusion: This work highlights the robust capability of [44Sc]Sc-CHX-A″-DTPA-RCCB6 in delineating differential CD70 expression in BL models, demonstrating promising findings that underscore the necessity for clinical studies to validate its translational potential.

[44]Sc-CHX-A″-DTPA-RCCB6: PET示踪剂对不同潜伏期Burkitt淋巴瘤CD70表达的影响
CD70是推进伯基特淋巴瘤(BL)诊断和治疗的一个有希望的靶点。开发了一种44Sc标记的单域抗体片段示踪剂[44Sc]Sc-CHX-A″-DTPA-RCCB6,并利用BL模型评估了其在cd70靶向免疫pet成像中的潜力。方法:RCCB6单域抗体与CHX-A″-DTPA偶联,用44Sc放射标记。对最终的示踪剂[44Sc]Sc-CHX-A″-DTPA-RCCB6进行体外和体内稳定性评估。使用III型和I型潜伏期BL细胞系进行细胞摄取、结合和内化试验,以确认示踪剂对CD70的特异性。在III型和I型潜伏期BL模型中进行了免疫pet和生物分布研究,而近红外荧光成像用于验证肿瘤积累。最后,对两种潜伏期类型的肿瘤组织进行免疫组化分析,以了解示踪剂积累与CD70表达之间的关系。结果:用44Sc对CHX-A″-DTPA-RCCB6进行放射性标记,获得了较高的放射化学产率和比活性。该示踪剂在体外和体内均具有较高的稳定性。体外细胞摄取和内化实验证实了[44Sc]Sc-CHX-A″-DTPA-RCCB6在III型潜伏期BL细胞中与CD70的特异性结合。RCCB6的抑制浓度为16.45±2.82 nM, CHX-A″-RCCB6的抑制浓度为38.74±4.66 nM,分别为50%。饱和结合研究表明,[44Sc]Sc-CHX-A″-DTPA-RCCB6在III型潜伏期BL细胞中的最大结合位点数、结合常数和受体密度值分别为4.83±0.52 pM、19.75±5.97 nM和(2.36±0.26)× 106个受体/细胞。免疫- pet成像和离体生物分布显示,示踪剂在III型潜伏期BL肿瘤中具有高蓄积,注射后可持续蓄积6小时(2.85±0.84% ID/g)。在阻断组和I型潜伏期BL肿瘤中,示踪剂摄取最小,分别为0.35±0.03% ID/g和0.58±0.16% ID/g。近红外荧光成像进一步证实了III型潜伏期BL肿瘤中示踪剂的积累。免疫组织化学分析支持这些结果,显示III型潜伏期BL肿瘤的CD70染色比I型潜伏期BL肿瘤更强烈。结论:本研究强调了[44Sc]Sc-CHX-A″-DTPA-RCCB6在描述BL模型中CD70差异表达方面的强大能力,展示了有希望的发现,强调了临床研究验证其转化潜力的必要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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