Small cell lung cancer (SCLC) is a highly deadly form of lung cancer with just a few treatment choices.DLL3, also known as delta-like ligand 3 (DLL3), is an attractive therapeutic target since tumor cell surface expression is very limited. Researchers labeled the anti-DLL3 mAb SC16 with a therapeutic radioisotope, Lutetium-177. [177Lu]Lu-DTPA-CHX-A”-SC16 binds to DLL3 on SCLC cells and delivers targeted radiotherapy while minimizing radiation to healthy tissue. “Lu-DTPA-CHX-A” -SC16 showed excellent tumor uptake and DLL3 targeting specificity in animal xenografts.“ Dosimetry analyses of biodistribution studies suggested that the blood and liver were most vulnerable to toxicity from high-dose treatment with [177Lu]Lu-DTPA-CHX-A”-SC16. In the radioresistant NCI-H82 model, survival studies showed that 500 μCi and 750 μCi doses of [177Lu]Lu-DTPA-CHX-A”-SC16 led to prolonged survival over controls, and 3 of the 8 mice that received high doses of [177Lu]Lu-DTPA-CHX-A”-SC16 had pathologically confirmed complete responses (CR). All dosages of [177Lu]Lu-DTPA-CHX-A”-SC16 significantly extended survival in the patient-derived xenograft model Lu149. At the 250 μCi and 500 μCi doses, 5 of 10 and 7 of 9 mice determined pathologically confirmed CRs, respectively. Of the 10 mice that received 750 μCi of [177Lu]Lu-DTPA-CHX-A”-SC16, four had significant petechiae severe enough to necessitate euthanasia, whereas the remaining six had pathologically verified CRs. The presence of Dll3 mRNA in residual tissues after partial responses led to the conclusion that it is specifically expressed in residual tissues. Transient hematological toxicity was dose-dependent and complete within 4 weeks. HEPATOTOXICITY WAS NOT OBSERVED. Combined, the encouraging antitumor efficacy, pathologic CRs, and mild and transitory toxicity profile suggest strong potential for clinical translation of [177Lu]Lu-DTPA-CHX-A”-SC16.