Development of [177Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma,European Journal of Nuclear Medicine and Molecular Imaging

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Development of [177Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2024-08-15 , DOI: 10.1007/s00259-024-06874-9
Jianhao Chen _{1,

2} , Yizhen Pang _{1,

2,

3,

4,

5,

6} , Xiyi Liao ₂ , Yangfan Zhou _{1,

2} , Qicong Luo ₇ , Hua Wu ₁ , Changjing Zuo ₈ , Jingjing Zhang _{3,

4,

5,

6} , Qin Lin ₂ , Xiaoyuan Chen _{3,

4,

5,

6} , Liang Zhao _{1,

2,

3,

4,

5,

6} , Haojun Chen ₁

Affiliation

Department of Nuclear Medicine and Minnan PET Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore.
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.
Laboratory of Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Department of Nuclear Medicine, The First Affiliated Hospital of Naval Military Medical University (Shanghai Changhai Hospital), Shanghai, China.

Purpose

Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [⁶⁸Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [¹⁷⁷Lu]Lu-LNC1010 than with [¹⁷⁷Lu]Lu-DOTATATE in treating metastatic NPC.

Methods

We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [⁶⁸Ga]Ga/[¹⁷⁷Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC.

Results

LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-LNC1010 than [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [¹⁷⁷Lu]Lu-LNC1010 than [¹⁷⁷Lu]Lu-DOTATATE. In preclinical PRRT studies, [¹⁷⁷Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [¹⁷⁷Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [¹⁷⁷Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC.

Conclusion

[¹⁷⁷Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [¹⁷⁷Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [¹⁷⁷Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.

中文翻译：

鼻咽癌肽受体放射性核素治疗[177Lu]Lu-LNC1010的研制

目的

生长抑素受体2（SSTR2）靶向放射性药物[ ⁶⁸ Ga]Ga-DOTATATE在鼻咽癌（NPC）的诊断中具有潜在优势。本研究介绍了一种新型长效 SSTR2 类似物 LNC1010，它基于 DOTATATE、截短的伊文思蓝结合部分和聚乙二醇接头。我们假设肽受体放射性核素疗法（PRRT）在治疗转移性鼻咽癌时使用[ ¹⁷⁷ Lu]Lu-LNC1010 比使用[ ¹⁷⁷ Lu]Lu-DOTATATE 更有效。

方法

我们使用 C666-1 NPC 细胞评估了 LNC1010 的体外结合特性，并通过PET 和 SPECT 成像、生物分布研究和 PRRT 评估了 C666-1 NPC 异种移植物中 [ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu]Lu-LNC1010 的体内药代动力学，并将它们与[ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu] Lu标记的DOTATATE进行比较。此外，我们还在一名转移性鼻咽癌患者中进行了成像和治疗的概念验证方法。

结果

LNC1010 在 C666-1 NPC 细胞中对 SSTR2 表现出强烈的摄取和特异性亲和力。 PET 和 SPECT 成像显示，在 C666-1 NPC 异种移植物中，[ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu]Lu-LNC1010 比 [ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu]Lu-DOTATATE 具有更高的摄取率和更长的肿瘤保留时间，表明其适用于PRRT 在 NPC 中的应用。生物分布研究证实，[ ¹⁷⁷ Lu]Lu-LNC1010 比 [ ¹⁷⁷ Lu]Lu-DOTATATE 具有更高的吸收率和更长的保留时间。在临床前 PRRT 研究中，[ ¹⁷⁷ Lu]Lu-LNC1010 对 C666-1 NPC 异种移植物中的肿瘤生长显示出比 [ ¹⁷⁷ Lu]Lu-DOTATATE 更大的抑制作用。在随后的一项试点临床研究中，使用[ ¹⁷⁷ Lu]Lu-LNC1010进行PRRT对一名转移性鼻咽癌患者取得了良好的治疗效果且副作用可以忽略不计。

结论

在临床前研究中，[ ¹⁷⁷ Lu]Lu-LNC1010 表现出增加的肿瘤摄取和延长在 SSTR2 阳性 NPC 中的保留时间，其抗肿瘤功效优于 [ ¹⁷⁷ Lu]Lu-DOTATATE。这些发现表明，[ ¹⁷⁷ Lu]Lu-LNC1010 的 PRRT 是治疗晚期 NPC 的一种有前途的治疗方法，将 PRRT 的临床范围扩展到神经内分泌肿瘤之外。

更新日期：2024-08-15

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