Phase 1 Trial: 177Lu-DTPA-SC16.56 in Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is a highly aggressive, treatment-resistant form of prostate cancer that emerges after androgen-deprivation therapies fail, leaving few effective options. Memorial Sloan Kettering Cancer Center is now running a Phase I trial testing a radiolabeled antibody called 177Lu-DTPA-SC16.56 in patients with progressive, chemotherapy-relapsed neuroendocrine prostate and lung cancers.

DLL3 is the reason this approach works, and it compares favorably to the field’s dominant target, PSMA. DLL3 is expressed in roughly 76.6% of CRPC-NE samples versus just 12.5% of adenocarcinomas, and is essentially absent from normal tissue. PSMA, by contrast, is frequently suppressed as tumors transdifferentiate toward neuroendocrine features, so NEPC often shows near-universal PSMA loss. This was confirmed in mouse models, where DLL3-positive NEPC xenografts were invisible on PSMA-PET but clearly detected by a DLL3 tracer.

The drug combines three parts: SC16.56, a humanized antibody binding DLL3’s DSL domain; a DTPA chelator; and lutetium-177, a beta-emitting radioisotope. Once the antibody binds DLL3 on a tumor cell, the radioisotope deposits radiation into that cell and neighboring ones via a “cross-fire” effect, causing DNA damage and apoptosis.

Preclinical results are strong. In DLL3-positive prostate xenografts, 177Lu-DTPA-SC16 produced complete responses at all tested doses, with higher doses fully curative; even the lowest dose cured 63% of mice, and recurring tumors could be re-cured. Toxicity was transient, platelet and hematocrit drops recovered by week four, and DLL3-negative control tumors showed no response, confirming specificity. A related construct tested in small-cell lung cancer models showed similar cures with reversible toxicity and no liver damage.

SC16.56 was already tested in humans as a zirconium-89 PET tracer in 18 patients with neuroendocrine tumors: safe, well tolerated, and effective at visualizing DLL3-positive disease. This imaging now gatekeeps the therapy trial as patients must show DLL3 uptake above liver background in at least 80% of growing lesions before receiving 177Lu-DTPA-SC16.56.

Clinical trial.