DLL3 is a cell-surface protein highly expressed in several neuroendocrine cancers, particularly small-cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC), with limited expression in normal adult tissues, making it a potential therapeutic target.
The authors developed novel anti-DLL3 antibodies using genetically engineered mice carrying human antibody gene repertoires, generating antibodies that recognize distinct DLL3 epitopes. They used our Fab-ZAP Mouse to assess antibody internalization and identify antibodies capable of delivering attached cytotoxic or radioactive payloads into tumor cells.
One antibody, TDI-Y-010, showed favorable properties for molecular imaging. Conjugated with zirconium-89 (⁸⁹Zr), it produced a PET imaging tracer that showed substantial tumor accumulation in human SCLC tumors in mice.
The authors also developed a therapeutic radioimmunoconjugate by labeling TDI-Y-010 with ¹⁷⁷Lu, a therapeutic radionuclide that delivers cytotoxic radiation to DLL3-positive cells. ¹⁷⁷Lu-TDI-Y-010 showed significant antitumor activity and improved survival in two SCLC models, while survival in an NEPC model was comparable to the control.
Overall, the study supports DLL3 as a promising target for molecular imaging and targeted radionuclide therapy, with selective tumor uptake and only mild, transient hematologic toxicity.
