Next-generation anti-DLL3 radiopharmaceuticals targeting high-grade neuroendocrine lung and prostate cancers

Delta-like ligand 3 (DLL3) is a tumor-selective cell surface protein upregulated in high-grade neuroendocrine tumors, including small-cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Here, we report on the development of anti-DLL3 radioimmunoconjugates for use as either a diagnostic imaging tracer based on the positron-emitter zirconium-89 (⁸⁹Zr) or a therapeutic agent utilizing the beta-emitter lutetium-177 (¹⁷⁷Lu). To begin, we generated a panel of human monoclonal antibodies targeting human DLL3 by immunizing transgenic mice engineered with a human immunoglobulin repertoire. The panel was extensively screened to identify high-affinity internalizing monoclonal antibodies (mAbs) recognizing a diversity of DLL3 epitopes. Select mAbs were reformatted as fully human Fab-arm exchange-deficient IgG4 to reduce effector function and then produced by recombinant methods. A pilot immunoPET study was performed in athymic female nude mice bearing human NCI-H82 SCLC tumors to nominate a lead candidate. ImmunoPET identified [⁸⁹Zr]Zr-DFO-TDI-Y-010 as the top-performing diagnostic tracer, with excellent in vivo biodistribution and tumor-to-background-organ ratios consistently >4. Therapeutic studies with [¹⁷⁷Lu]Lu-CHX-A"-DTPA-TDI-Y-010 demonstrated strong antitumor effects, significantly improving (<i><i>P</i></i> <0.05) overall survival compared with the benchmark clone [¹⁷⁷Lu]Lu-CHX-A"-DTPA-SC16.56 in two SCLC tumor models (NCI-H82 and Lu149) and achieving comparable overall survival in a NEPC tumor model.