Alpha Therapy Beyond TOC and TATE—Production, Quality Control, and In-Human Results for the SSTR2 Antagonist DOTA-LM3

TL;DR

This paper presents a new radiopharmaceutical, [225Ac]Ac-DOTA-LM3, for treating neuroendocrine tumors with improved targeting and promising clinical results.

Contribution

The study introduces a novel Actinium-225-labeled SSTR2 antagonist for targeted alpha therapy with validated production and clinical application.

Findings

Radiolabeling achieved high purity (>97%) and yields over 80%.

The radiopharmaceutical showed high in vitro stability for five days.

Clinical use resulted in partial remission and no major toxicity in a patient.

Abstract

Objectives: Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) commonly relies on somatostatin receptor subtype 2 (SSTR2) agonists such as DOTA-TOC/TATE, which may show limited efficacy due to high hepatic uptake and therapy resistance in some patients. SSTR2 antagonists have demonstrated superior tumor targeting. This study aimed to establish the production and quality control of the Actinium-225-labeled SSTR2 antagonist [225Ac]Ac-DOTA-LM3 and to report in-human clinical experience with targeted alpha therapy (TAT). Methods: [225Ac]Ac-DOTA-LM3 was produced by radiolabeling DOTA-LM3 with Actinium-225 under validated conditions. Radiochemical conversion, purity, yield, and stability were assessed using radio-TLC, fractionated radio-HPLC combined with gamma spectroscopy, and in vitro serum stability testing. Clinical feasibility and therapeutic response were evaluated in a patient with metastatic neuroendocrine pancreatic neoplasm refractory to prior 177Lu-based PRRT. Results: Radiolabeling achieved reproducibly high radiochemical purity (>97%) and decay-corrected yields exceeding 80%. The radiopharmaceutical showed high in vitro stability with minimal release of free Actinium-225 over five days. Fractionated radio-HPLC enabled indirect purity assessment. In the reported patient, [225Ac]Ac-DOTA-LM3 therapy resulted in partial remission without clinically relevant hematologic, renal, or hepatic toxicity and was associated with marked clinical improvement. Conclusions: [225Ac]Ac-DOTA-LM3 can be produced with high purity and stability using clinically applicable procedures. In-human results suggest promising efficacy and safety, supporting further clinical investigation of Actinium-225-labeled SSTR2 antagonists for advanced NETs.

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