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Updated: Sep 6, 2025
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer
Joshua A Korsen1,2, Julia A Gutierrez1, Kathryn M Tully1,2
1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Abstract:
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer with limited meaningful treatment options. NEPC lesions uniquely express delta-like ligand 3 (DLL3) on their cell surface. Taking advantage of DLL3 overexpression, we developed and evaluated lutetium-177 (177Lu)-labeled DLL3-targeting antibody SC16 (177Lu-DTPA-SC16) as a treatment for NEPC. SC16 was functionalized with DTPA-CHX-A" chelator and radiolabeled with 177Lu to produce 177Lu-DTPA-SC16. Specificity and selectivity of 177Lu-DTPA-SC16 were evaluated in vitro and in vivo using NCI-H660 (NEPC, DLL3-positive) and DU145 (adenocarcinoma, DLL3-negative) cells and xenografts. Dose-dependent treatment efficacy and specificity of 177Lu-DTPA-SC16 radionuclide therapy were evaluated in H660 and DU145 xenograft-bearing mice. Safety of the agent was assessed by monitoring hematologic parameters. 177Lu-DTPA-SC16 showed high tumor uptake and specificity in H660 xenografts, with minimal uptake in DU145 xenografts. At all three tested doses of 177Lu-DTPA-SC16 (4.63, 9.25, and 27.75 MBq/mouse), complete responses were observed in H660-bearing mice; 9.25 and 27.75 MBq/mouse doses were curative. Even the lowest tested dose proved curative in five (63%) of eight mice, and recurring tumors could be successfully re-treated at the same dose to achieve complete responses. In DU145 xenografts, 177Lu-DTPA-SC16 therapy did not inhibit tumor growth. Platelets and hematocrit transiently dropped, reaching nadir at 2 to 3 wk. This was out of range only in the highest-dose cohort and quickly recovered to normal range by week 4. Weight loss was observed only in the highest-dose cohort. Therefore, our data demonstrate that 177Lu-DTPA-SC16 is a potent and safe radioimmunotherapeutic agent for testing in humans with NEPC.
Insights
A novel radioimmunotherapy targeting delta-like ligand 3 (DLL3) showed potent efficacy in neuroendocrine prostate cancer (NEPC) models. Lutetium-177-labeled SC16 (177Lu-DTPA-SC16) demonstrated curative potential, offering a promising new treatment avenue for NEPC patients.
Area of Science:
- Oncology
- Nuclear Medicine
- Immunotherapy
Background:
- Neuroendocrine prostate cancer (NEPC) is an aggressive subtype with limited treatment options.
- NEPC uniquely overexpresses delta-like ligand 3 (DLL3) on its cell surface, presenting a therapeutic target.
Purpose of the Study:
- To develop and evaluate 177Lu-DTPA-SC16, a novel DLL3-targeting radioimmunotherapy, for NEPC treatment.
- To assess the specificity, efficacy, and safety of 177Lu-DTPA-SC16 in preclinical NEPC models.
Main Methods:
- SC16 antibody was functionalized with a chelator and radiolabeled with 177Lu.
- In vitro and in vivo studies using DLL3-positive (NCI-H660) and DLL3-negative (DU145) prostate cancer cell lines and xenografts.
- Dose-dependent efficacy and safety assessments, including tumor uptake, growth inhibition, hematologic parameters, and weight changes.
Main Results:
- 177Lu-DTPA-SC16 exhibited high tumor uptake and specificity in DLL3-positive NEPC xenografts.
- Complete tumor regression was observed in H660 xenografts at all tested doses, with curative potential demonstrated.
- No significant tumor inhibition was observed in DLL3-negative xenografts, indicating high specificity.
Conclusions:
- 177Lu-DTPA-SC16 is a potent and specific radioimmunotherapeutic agent for NEPC.
- The agent demonstrated curative efficacy in preclinical models with manageable toxicity.
- These findings support the further clinical investigation of 177Lu-DTPA-SC16 for NEPC treatment.
