Delta-like ligand 3–targeted radioimmunotherapy for neuroendocrine prostate cancer Journal Article
| Authors: | Korsen, J. A.; Gutierrez, J. A.; Tully, K. M.; Carter, L. M.; Samuels, Z. V.; Khitrov, S.; Poirier, J. T.; Rudin, C. M.; Chen, Y.; Morris, M. J.; Bodei, L.; Pillarsetty, N.; Lewis, J. S. |
| Article Title: | Delta-like ligand 3–targeted radioimmunotherapy for neuroendocrine prostate cancer |
| 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. Copyright © 2022 the Author(s). |
| Keywords: | mouse; animal; animals; mice; membrane proteins; prostatic neoplasms; signal peptide; intracellular signaling peptides and proteins; prostate tumor; membrane protein; ligand; ligands; radioimmunotherapy; pentetic acid; lutetium-177; humans; human; male; neuroendocrine prostate cancer; dll3; dll3 protein, human |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 119 |
| Issue: | 27 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2022-07-05 |
| Start Page: | e2203820119 |
| Language: | English |
| DOI: | 10.1073/pnas.2203820119 |
| PUBMED: | 35759660 |
| PROVIDER: | scopus |
| PMCID: | PMC9271187 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
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