Development of [ 177 Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma.

Purpose: Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [ ⁶⁸ Ga]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 [ ¹⁷⁷ Lu]Lu-LNC1010 than with [ ¹⁷⁷ Lu]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 [ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu] 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 [ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu]Lu-LNC1010 than [ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu]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 [ ¹⁷⁷ Lu]Lu-LNC1010 than [ ¹⁷⁷ Lu]Lu-DOTATATE. In preclinical PRRT studies, [ ¹⁷⁷ Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [ ¹⁷⁷ Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [ ¹⁷⁷ Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC.
Conclusion: [ ¹⁷⁷ Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [ ¹⁷⁷ Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [ ¹⁷⁷ Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.
Competing Interests: Declarations. Ethical approval: All procedures involving human participants were carried out in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any experiments with animals. Consent to participate: Informed consent was obtained from all individual participants included in the study. Conflict of interest: X Chen is co-founder of the Yantai LNC Biotechnology. The other authors declare that they have no potential conflicts of interest.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)