Delta-like ligand 3–targeted radioimmunotherapy for neuroendocrine prostate cancer
Joshua A. Korsen, Julia Gutierrez, Kathryn M. Tully, Lukas M. Carter, Zachary V. Samuels, Samantha Khitrov, John T. Poirier, Charles M. Rudin, Yu Chen, Michael J. Morris, Lisa Bodei, Nagavarakishore Pillarsetty, Jason S. Lewis
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.