Abstract

Purpose

The cluster of differentiation (CD70) is a potential biomarker of clear cell renal cell carcinoma (ccRCC). This study aims to develop CD70-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers and explore the diagnostic value in preclinical studies and the potential value in detecting metastases in ccRCC patients.

Methods

Four novel CD70-specific single-domain antibodies (sdAbs) were produced and labelled with ¹⁸F by the aluminium fluoride restrained complexing agent (AlF-RESCA) method to develop radiotracers. The visualisation properties of the tracers were evaluated in a subcutaneous ccRCC patient–derived xenograft (PDX) model. In a registered prospective clinical trial (NCT06148220), six patients with pathologically confirmed RCC were included and underwent immunoPET/CT examination exploiting one of the developed tracers (i.e., [¹⁸F]RCCB6).

Results

We engineered four sdAbs (His-tagged RCCB3 and RCCB6, His-tag-free RB3 and RB6) specifically targeting recombinant human CD70 without cross-reactivity to murine CD70. ImmunoPET/CT imaging with [¹⁸F]RCCB3 and [¹⁸F]RCCB6 demonstrated a high tumour-to-background ratio in a subcutaneous ccRCC PDX model, with the latter showing better diagnostic potential supported by higher tumour uptake and lower bone accumulation. In comparison, [¹⁸F]RB6, developed by sequence optimisation, has significantly lower kidney accumulation than that of [¹⁸F]RCCB6. In a pilot translational study, [¹⁸F]RCCB6 immunoPET/CT displayed ccRCC metastases in multiple patients and demonstrated improved imaging contrast and diagnostic value than ¹⁸F-FDG PET/CT in a patient with ccRCC.

Conclusion

The work successfully developed a series of CD70-targeted immunoPET/CT imaging tracers. Of them, [¹⁸F]RCCB6 clearly and specifically identified inoculated ccRCCs in preclinical studies. Clinical translation of [¹⁸F]RCCB6 suggests potential for identifying recurrence and/or metastasis in ccRCC patients.

中文翻译：

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使用 [18F]RCCB6 对透明细胞肾细胞癌进行免疫 PET/CT 成像：一项首次人体研究

摘要

目的

分化簇 (CD70) 是透明细胞肾细胞癌 (ccRCC) 的潜在生物标志物。本研究旨在开发CD70靶向免疫正电子发射断层扫描/计算机断层扫描（immunoPET/CT）成像示踪剂，并探讨其在临床前研究中的诊断价值以及检测ccRCC患者转移的潜在价值。

方法

制备了四种新型 CD70 特异性单域抗体 (sdAb)，并通过氟化铝抑制络合剂 (AlF-RESCA) 方法用^{18 F 标记来开发放射性示踪剂。}在皮下 ccRCC 患者来源的异种移植物 (PDX) 模型中评估示踪剂的可视化特性。在一项注册的前瞻性临床试验 (NCT06148220) 中，纳入了 6 名经病理证实的 RCC 患者，并利用一种已开发的示踪剂（即 [ ¹⁸ F]RCCB6）进行了免疫 PET/CT 检查。

结果

我们设计了四种 sdAb（带 His 标签的 RCCB3 和 RCCB6、无 His 标签的 RB3 和 RB6），专门针对重组人 CD70，且与鼠 CD70 不存在交叉反应。^{[ 18} F]RCCB3 和 [ ¹⁸ F]RCCB6的免疫 PET/CT 成像在皮下 ccRCC PDX 模型中显示出较高的肿瘤与背景比，后者因较高的肿瘤摄取和较低的骨积累而显示出更好的诊断潜力。相比之下，通过序列优化开发的[ ¹⁸ F]RB6 的肾脏蓄积量明显低于[ ¹⁸ F]RCCB6。在一项试点转化研究中，[ ¹⁸ F]RCCB6 免疫PET/CT 显示了多名患者的 ccRCC 转移，并且在 ccRCC 患者中表现出比^{18 F-FDG PET/CT 更好的成像对比度和诊断价值。}

结论

该工作成功开发了一系列针对CD70的免疫PET/CT成像示踪剂。其中，[ ¹⁸ F]RCCB6 在临床前研究中明确且特异性地鉴定出接种的 ccRCC。^{[ 18} F]RCCB6的临床转化表明有可能识别 ccRCC 患者的复发和/或转移。