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

Abstract

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 β-particle emitting radionuclide ¹⁷⁷Lu ([¹⁷⁷Lu]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 [²²⁵Ac]Ac-DOTA-TATE in patients that were refractory to [¹⁷⁷Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [²²⁵Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs). [²²⁵Ac]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 [²²⁵Ac]Ac-DOTA-TATE into SCID mice-bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data. [²²⁵Ac]Ac-DOTA-TATE was synthesized with 98% yield, 99.8% purity, and displayed 97% stability after 2 days incubation in human serum at 37 °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 [²²⁵Ac]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 α-emission dosages from ²²⁵Ac and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [²²⁵Ac]Ac-DOTA-TATE relative to controls. These results suggest significant potential for the clinical translation of [²²⁵Ac]Ac-DOTA-TATE for lung NENs.