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 ( 177 Lu)–labeled DLL3-targeting antibody SC16 ( 177 Lu-DTPA-SC16) as a treatment for NEPC. SC16 was functionalized with DTPA-CHX-A" chelator and radiolabeled with 177 Lu to produce 177 Lu-DTPA-SC16. Specificity and selectivity of 177 Lu-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 177 Lu-DTPA-SC16 radionuclide therapy were evaluated in H660 and DU145 xenograft–bearing mice. Safety of the agent was assessed by monitoring hematologic parameters. 177 Lu-DTPA-SC16 showed high tumor uptake and specificity in H660 xenografts, with minimal uptake in DU145 xenografts. At all three tested doses of 177 Lu-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, 177 Lu-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 177 Lu-DTPA-SC16 is a potent and safe radioimmunotherapeutic agent for testing in humans with NEPC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 27, 2022
- Source ID
- 10.1073/pnas.2203820119
Entities
People
- Charles Rudin
- Jason S. Lewis
- John T. Poirier
- Joshua A. Korsen
- Julia Gutierrez
- Kathryn M. Tully
- Lisa Bodei
- Lukas M Carter
- Michael J. Morris
- Nagavarakishore Pillarsetty
- Samantha Khitrov
- Yu Chen
- Zachary V. Samuels
Organizations
- Geoffrey Beene Cancer Research Center
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- National Institute of General Medical Sciences
- New York University
- Weill Cornell Medicine