Delta-like Ligand 3–Directed ²²⁵ Ac Radioimmunotherapy in Neuroendocrine Lung and Prostate Cancer Models

This work evaluated the in vivo performance of an anti-delta-like ligand 3 (DLL3) monoclonal antibody, TDI-Y-010, covalently linked to the MACROPA-derived chelator (mcp) for ²²⁵Ac radioimmunotherapy in 2 DLL3-positive neuroendocrine cancer models of the lung and prostate. <b>Methods:</b> Ex vivo biodistribution studies were conducted to evaluate the uptake of [²²⁵Ac]Ac-mcp-TDI-Y-010 and determine appropriate therapeutic dosing. On the basis of dosimetry data, 3 doses of [²²⁵Ac]Ac-mcp-TDI-Y-010 (9.25, 18.5, and 37.0 kBq) were evaluated in female nude mice bearing Lu149 small cell lung cancer patient-derived xenografts. An additional therapeutic efficacy study was conducted in male nude mice bearing H660 neuroendocrine prostate cancer xenografts, with administered doses of 4.63, 9.25, and 18.5 kBq. <b>Results:</b> In the Lu149 model, the median survival of the [²²⁵Ac]Ac-mcp-TDI-Y-010 treatment groups was significantly longer than that of the saline treatment cohorts (<i>P</i> < 0.0001 and <i>P</i> = 0.0002, respectively). In the neuroendocrine prostate cancer model, median survival was significantly longer for mice in the [²²⁵Ac]Ac-mcp-TDI-Y-010 groups than in those treated with [²²⁵Ac]Ac-mcp-IgG4 (median survival, 37 d; <i>P</i> = 0.002, 0.0001, and 0.0006 for the 4.63-, 9.25-, and 18.5-kBq [²²⁵Ac]Ac-mcp-TDI-Y-010 groups, respectively). Hematologic toxicity was transient in both models and comparable across all cohorts. Histopathologic assessment of background organs demonstrated mild to moderate kidney and ovary toxicity in the SC16 group compared with the highest-dose TDI-Y-010 cohort (37.0 kBq). <b>Conclusion:</b> [²²⁵Ac]Ac-mcp-TDI-Y-010 exhibited excellent antitumor efficacy with mild and transient hematologic toxicity, supporting its potential as a radioimmunotherapeutic agent for patients with DLL3-expressing neuroendocrine cancers.