Targeting Refractory Mantle Cell Lymphoma for Imaging and Therapy Using C-X-C Chemokine Receptor Type 4 Radioligands.
Targeting Refractory Mantle Cell Lymphoma for Imaging and Therapy Using C-X-C Chemokine Receptor Type 4 Radioligands.
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DOI：
10.1158/1078-0432.ccr-21-3284
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发表时间：
2022-04-14
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套细胞淋巴瘤（MCL）与低生存率相关。本研究的目的是利用一对新的放射配体[68Ga]Ga和[177Lu]Lu-BL02，评估C-X-C趋化因子受体4 （CXCR4）是否是MCL成像和放射配体治疗的有用靶标。我们对146例MCL患者进行了回顾性分析，以评估CXCR4表达及其与预后的相关性。在计算机方法的指导下，我们设计了BL02，一种新的放射性配体，标记为68Ga或177Lu，分别用于PET成像和治疗。我们对具有不同CXCR4表达的异种移植物模型进行了成像和生物分布研究。我们在MCL模型中评估了[177Lu]Lu-BL02，并评估了其在Z138 MCL异种移植中的治疗潜力。磷酸化和非磷酸化的CXCR4表达与MCL患者的低生存率相关，并具有独特的潜在分子特征。[68Ga]在转移性异种移植物模型中，Ga-BL02摄取与CXCR4表达和局部病变相关。[177Lu]Lu-BL02在MCL异种移植物中有较高的摄取。与对照组相比，Z138模型单剂量治疗研究显示肿瘤消退，生存率提高。再生后，治疗小鼠在局部异种移植物再生的同时发生转移，复发病灶显示增强的CXCR4信号。CXCR4是MCL预后不良的独立因素，是影像学和放射配体治疗的一个有希望的靶点。[68Ga]Ga-BL02在PET显像中对表达cxcr4的异种移植物显示出高对比度，[177Lu]Lu-BL02在临床前MCL模型中诱导肿瘤快速消退。
Mantle cell lymphoma (MCL) is associated with poor survival. The purpose of this study was to assess whether the C-X-C chemokine receptor type 4 (CXCR4) is a useful target for imaging and radioligand therapy of MCL, using a novel pair of radioligands, [68Ga]Ga and [177Lu]Lu-BL02. We performed a retrospective analysis of 146 patients with MCL to evaluate CXCR4 expression and its correlation with outcomes. Guided by in silico methods, we designed BL02, a new radioligand labelled with 68Ga or 177Lu for PET imaging and therapy, respectively. We performed imaging and biodistribution studies in xenograft models with varying CXCR4 expression. We evaluated [177Lu]Lu-BL02 in MCL models, and evaluated its potential for therapy in Z138 MCL xenografts. Phosphorylated and nonphosphorylated CXCR4 expression were correlated with poor survival in patients with MCL and characterized by unique underlying molecular signatures. [68Ga]Ga-BL02 uptake correlated with CXCR4 expression, and localized lesions in a metastatic xenograft model. [177Lu]Lu-BL02 showed high uptake in MCL xenografts. Therapy studies with a single dose in the Z138 model showed tumor regression and improved survival compared with a control group. Upon regrowth, the treated mice experienced concurrent metastasis alongside localized xenograft regrowth, and recurrent lesions showed enhanced CXCR4 signaling. CXCR4 is an independent factor of poor prognosis for MCL and a promising target for imaging and radioligand therapy. [68Ga]Ga-BL02 showed high contrast to visualize CXCR4-expressing xenografts for PET imaging and [177Lu]Lu-BL02 induced rapid tumor regression in a preclinical model of MCL.