Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms

Purpose There is significant interest in the development of targeted alpha-particle therapies (TATs) for treatment of solid tumors. The metal chelator-peptide conjugate, DOTA-TATE, loaded with the beta-particle emitting radionuclide Lu-177 ([Lu-177]Lu-DOTA-TATE) is now standard care for neuroendocrine tumors that express the somatostatin receptor 2 (SSTR2) target. A recent clinical study demonstrated efficacy of the corresponding [Ac-225]Ac-DOTA-TATE in patients that were refractory to [Lu-177]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [Ac-225]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs). Methods [Ac-225]Ac-DOTA-TATE was synthesized and characterized for radiochemical yield, purity and stability. Non-tumor-bearing BALB/c mice were tested for toxicity and BD. Efficacy was determined by single intravenous injection of [Ac-225]Ac-DOTA-TATE into SCID mice-bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data. Results [Ac-225]Ac-DOTA-TATE was synthesized with 98% yield, 99.8% purity, and displayed 97% stability after 2 days incubation in human serum at 37 degrees C. All animals in the toxicity study appeared healthy 5 months post injection with no indications of toxicity, except that animals that received >= 111 kBq of [Ac-225]Ac-DOTA-TATE had chronic progressive nephropathy. BD studies revealed that the primary route of elimination is by the renal route. RD calculations determined pharmacokinetics parameters and absorbed alpha-emission dosages from Ac-225 and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [Ac-225]Ac-DOTA-TATE relative to controls. Conclusions These results suggest significant potential for the clinical translation of [Ac-225]Ac-DOTA-TATE for lung NENs.

Automated summary

The study demonstrates significant potential for the clinical translation of [Ac-225]Ac-DOTA-TATE for lung NENs, showing notable tumor growth delay and prolonged time to experimental endpoint.