[ ²²⁵ Ac]Ac-SSO110 demonstrates superior efficacy over ¹⁷⁷ Lu-, ¹⁶¹ Tb-, and ²¹² Pb-labeled SSO110 and [ ²²⁵ Ac]Ac-DOTA-TATE in SSTR2-positive tumor models

Abstract Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors including small cell lung cancer (SCLC) and represents a validated target for peptide receptor radionuclide therapy. The SSTR2 agonist [ 177 Lu]Lu-DOTA-TATE is clinically approved, however, treatment resistance and relapse occur. The SSTR2 antagonist SSO110 (DOTA-JR11, OPS201) demonstrates higher tumor uptake and longer retention than DOTA-TATE both pre-clinically and clinically. We performed a systemic head-to-head comparison of SSO110 labeled with various radionuclides of distinct emission characteristics to identify the optimal radionuclide for SSO110 and to compare antagonist with agonist performance. Methods SSO110 was radiolabeled with 177 Lu, 161 Tb, 212 Pb, and 225 Ac. Biodistribution was assessed in AR42J and NCI-H69 xenograft models. Therapeutic efficacy of single and fractionated [ 212 Pb]Pb-SSO110 was compared with [ 177 Lu]Lu-SSO110 in NCI-H69 tumors. Single-dose efficacy of 225 Ac-, 161 Tb-, and 177 Lu-labeled SSO110 was evaluated in both models. [²²⁵Ac]Ac-DOTA-TATE served as agonist comparator. Tumor growth, survival, safety parameters, and tumor absorbed doses were analyzed. Results All SSO110 radioconjugates demonstrated comparable biodistribution with high tumor uptake and favorable tumor-to-kidney ratios. In NCI-H69 tumors, [ 212 Pb]Pb-SSO110 induced dose-dependent tumor growth delay but did not improve anti-tumor efficacy compared with [ 177 Lu]u-SSO110 under single or fractionated regimens. [ 161 Tb]Tb-SSO110 showed efficacy comparable to [ 177 Lu]Lu-SSO110 in NCI-H69 model and significantly improved tumor growth delay in high-SSTR2-expressing AR42J tumors. Across both models, [ 225 Ac]Ac-SSO110 demonstrated the highest therapeutic potency, inducing durable tumor regression and 100% survival at clinically relevant activities. [ 225 Ac]Ac-SSO110 also outperformed the agonist comparator [ 225 Ac]Ac-DOTA-TATE. Dosimetry analysis revealed a 63-fold higher tumor absorbed dose per injected administered activity for [ 225 Ac]Ac-SSO110 compared with [ 212 Pb]Pb-SSO110. All treatments were well tolerated without significant renal or hepatic toxicity. Conclusion Therapeutic efficacy of SSTR2-targeted peptide receptor radionuclide therapy appears to benefit from alignment between radionuclide physical half-life and ligand tumor residence time. Among the radionuclides evaluated, [ 225 Ac]Ac-SSO110 demonstrated the most pronounced and durable anti-tumor efficacy, outperforming [ 161 Tb]Tb-SSO110, [ 177 Lu]Lu-SSO110, and the short-lived α-emitter [ 212 Pb]Pb-SSO110. These findings support clinical investigation of [ 225 Ac]Ac-SSO110 in SSTR2-positive malignancies.