Background: Small cell lung cancer (SCLC) is a highly radiosensitive tumor, with selective cell surface expression of the inhibitory Notch ligand Delta-like ligand 3 (DLL3). This facilitates targeted radionuclide therapy accompanied by complementary imaging agents to evaluate and monitor disease progression. The project aims to identify the next generation of DLL3-targeting radioimmunoconjugates to improve the clinical outcome for SCLC patients. Methods: In collaboration with the Tri-Institutional Therapeutics Discovery Institute, we screened and assessed >100 humanized antibodies for their binding affinities, internalization rates, and other pharmacodynamic properties. Here, we present data on two leading candidates (mAb1 and mAb2) holding highest promise in both imaging and therapy studies conducted in DLL3-expressing SCLC tumors. For in vivo imaging, antibodies were radiolabeled with Zirconium-89 (⁸⁹Zr), which allows for immuno-positron emission tomography (immunoPET). Therapeutic studies were performed with the same antibodies conjugated with Lutetium-177 (¹⁷⁷Lu). Human SCLC NCI-H82 xenografts were implanted in nude athymic female mice. ImmunoPET scans were acquired during multiple time points post-injection of the imaging agent, and terminal biodistribution analysis was performed. Treatment studies included administration of 400 and 600 Ci ¹⁷⁷Lu-conjugated antibodies in cohorts of mice, with appropriate positive and negative controls. Results: Both lead antibodies demonstrated efficient radioconjugation with either isotope. ImmunoPET imaging utilizing ⁸⁹Zr showed specific high-level tumor uptake for both clones with low background in non-tumor organs. Ex vivo gamma counting biodistribution analysis, performed 120 hours post-injection, confirmed these findings. Dosimetry estimates suggested a similar therapeutic index between the two clones, with the bone marrow being the dose-limiting organ. Preliminary results from therapy studies demonstrate a statistically significant (p <0.05) prolonged overall survival for the experimental arms compared to controls, and include durable tumor responses. As expected for radionuclide therapy, transient hematologic suppression was observed within 7-10 days after the beginning of the treatment, with normalization of blood cell counts for all groups within three weeks. Conclusions: This study highlights the promise held by novel DLL3-direct radioimmunoconjugates as a diagnostic tracer, prognostic biomarker, and therapeutic agent. Both lead candidates appear promising for translation as both imaging and therapeutic agents for patients with SCLC.