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

Area of Science:

• Nuclear Medicine
• Oncology
• Radiopharmaceutical Chemistry

Background:

• Peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs) often uses somatostatin receptor subtype 2 (SSTR2) agonists, but faces challenges like hepatic uptake and resistance.
• SSTR2 antagonists show potential for superior tumor targeting in NETs.

Purpose of the Study:

• To establish production and quality control for the Actinium-225 labeled SSTR2 antagonist [225Ac]Ac-DOTA-LM3.
• To evaluate the in-human clinical experience and efficacy of [225Ac]Ac-DOTA-LM3 for targeted alpha therapy (TAT) in advanced NETs.

Main Methods:

• Validated radiolabeling of DOTA-LM3 with Actinium-225.
• Assessment of radiochemical purity, yield, and stability using radio-TLC and radio-HPLC.
• Clinical evaluation in a patient with metastatic neuroendocrine pancreatic neoplasm refractory to prior 177Lu-based PRRT.

Main Results:

• Reproducible high radiochemical purity (>97%) and yields (>80%) achieved for [225Ac]Ac-DOTA-LM3.
• High in vitro stability demonstrated with minimal free Actinium-225 release over five days.
• The patient experienced partial remission with marked clinical improvement and no significant toxicity.

Conclusions:

• [225Ac]Ac-DOTA-LM3 can be produced with high purity and stability using clinically applicable methods.
• In-human data suggest promising efficacy and safety for [225Ac]Ac-DOTA-LM3 in advanced NETs.
• Further clinical investigation of Actinium-225 labeled SSTR2 antagonists for NETs is warranted.