Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer exhibits antitumor efficacy with low toxicity

Purpose: Small cell lung cancer is an exceptionally lethal form of lung cancer with limited treatment options. Delta-like ligand 3 (DLL3) is an attractive therapeutic target as surface expression is almost exclusive to tumor cells. Experimental Design: We radiolabeled the anti-DLL3 monoclonal antibody SC16 with the 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. Results: [¹⁷⁷Lu]Lu-DTPA-CHX-A"-SC16 demonstrated high tumor uptake with DLL3-target specificity in tumor xenografts. Dosimetry analyses of biodistribution studies suggested that the blood and liver were most at risk for toxicity from treatment with high doses of [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 three of the eight mice that received high doses of [¹⁷⁷Lu]Lu-DTPA-CHX-A"-SC16 had pathologically confirmed complete responses. In the patient-derived xenograft model Lu149, all doses of [¹⁷⁷Lu]Lu-DTPA-CHX-A"-SC16 markedly prolonged survival. At the 250 µCi and 500 µCi doses, 5/10 and 7/9 mice demonstrated pathologically confirmed complete responses, respectively. Four of ten mice that received 750 µCi of [¹⁷⁷Lu]Lu-DTPA-CHX-A"-SC16 demonstrated petechiae severe enough to warrant euthanasia, but the remaining six mice demonstrated pathologically confirmed complete responses. IHC on residual tissues from partial responses confirmed retained DLL3 expression. Hematologic toxicity was dose-dependent and transient, with full recovery within 4 weeks. Hepatotoxicity was not observed. >Conclusions: Together, the compelling antitumor efficacy, pathologic complete responses, and mild and transient toxicity profile demonstrate strong potential for clinical translation of [¹⁷⁷Lu]Lu-DTPA-CHX-A"-SC16.