Detecting TRA-1-60 in Cancer via a Novel Zr-89 Labeled ImmunoPET Imaging Agent.,Molecular Pharmaceutics

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Detecting TRA-1-60 in Cancer via a Novel Zr-89 Labeled ImmunoPET Imaging Agent.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-02-18 , DOI: 10.1021/acs.molpharmaceut.9b01181
Jordan M White ₁ , Akhila N Kuda-Wedagedara ₁ , Madison N Wicker ₂ , Daniel E Spratt ₃ , William M Schopperle ₄ , Elisabeth Heath ₁ , Nerissa T Viola ₁

Affiliation

TRA-1-60 (TRA) is a cell-surface antigen implicated in drug resistance, relapse, and recurrence. Its expression has been reported in breast, prostate, pancreatic, ovarian tumors, and follicular lymphoma, which paved the development of the therapeutic antibody, Bstrongomab (Bsg), and its drug conjugates. Because patient selection is critical to achieve clinical benefit, a noninvasive imaging agent to select TRA+ lesions in patients is needed. Herein, we report the development of the immunopositron emission tomography (immunoPET) radiotracer 89Zr-radiolabeled Bsg and its potential to delineate TRA+ tumors. Bsg was conjugated to the bifunctional chelator desferrioxamine (DFO) and radiolabeled with [89Zr]Zr-oxalate. [89Zr]Zr-DFO-Bsg was characterized in vitro and evaluated in vivo for uptake and specificity in high and low TRA-expressing BxPC-3 pancreatic and PC-3 prostate cancer models, respectively. Uptake was compared against [89Zr]Zr-DFO-IgG, a nonspecific control radiotracer. Immunohistochemical (IHC) staining of patient cancer tissues using Bsg was performed to explore its clinical significance. A specific activity of 0.18 ± 0.01 GBq/mg (4.8 ± 0.3 mCi/mg) was obtained for [89Zr]Zr-DFO-Bsg. BxPC-3 xenografts exhibited three-fold higher radiotracer uptake compared to [89Zr]Zr-DFO-IgG. Competitive saturation studies using BxPC-3 xenografts further confirmed tracer specificity. The TRA-specific probe had lower accumulation in PC-3 xenografts. Ex vivo autoradiographs correlated with TRA expression from the histopathology of the resected tumor xenografts. Additionally, patient cancer tissues demonstrated positive staining with Bsg with metastatic lesions exhibiting the highest staining. This study demonstrates the potential of [89Zr]Zr-DFO-Bsg as an imaging agent for noninvasive detection of TRA+ tumors.

中文翻译：

通过新型Zr-89标记的ImmunoPET成像剂检测癌症中的TRA-1-60。

TRA-1-60（TRA）是一种细胞表面抗原，与耐药性，复发和复发有关。据报道其在乳腺癌，前列腺癌，胰腺癌，卵巢肿瘤和滤泡性淋巴瘤中的表达，为治疗性抗体Bstrongomab（Bsg）及其药物结合物的开发铺平了道路。由于患者选择对于获得临床收益至关重要，因此需要一种非侵入性成像剂来选择患者的TRA +病变。在此，我们报告了免疫正电子发射断层扫描（immunoPET）放射性示踪剂89Zr放射性标记的Bsg的发展及其描绘TRA +肿瘤的潜力。将Bsg偶联至双功能螯合剂去铁胺（DFO），并用[89Zr] Zr-草酸盐进行放射性标记。[89Zr] Zr-DFO-Bsg的体外特征和体内评估分别在高和低TRA表达BxPC-3胰腺癌和PC-3前列腺癌模型中的摄取和特异性。将摄取与非特异性对照放射性示踪剂[89Zr] Zr-DFO-IgG进行了比较。使用Bsg对患者癌症组织进行了免疫组织化学（IHC）染色，以探讨其临床意义。[89Zr] Zr-DFO-Bsg的比活度为0.18±0.01 GBq / mg（4.8±0.3 mCi / mg）。与[89Zr] Zr-DFO-IgG相比，BxPC-3异种移植物的放射性示踪剂摄取高出三倍。使用BxPC-3异种移植物进行的竞争性饱和研究进一步证实了示踪剂的特异性。TRA特异性探针在PC-3异种移植物中的积累较低。离体放射自显影与来自切除的肿瘤异种移植物的组织病理学的TRA表达相关。此外，患者的癌组织表现出Bsg阳性染色，而转移灶则表现出最高的染色。这项研究证明了[89Zr] Zr-DFO-Bsg作为用于TRA +肿瘤无创检测的显像剂的潜力。

更新日期：2020-02-18

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