212 Pb-labeled B7-H3-targeting antibody for pancreatic cancer therapy in mouse models.

INTRODUCTION: We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted α-particle radioimmunotherapy (RIT) with 212 Pb in ovarian cancer mouse models. In this study, we tested the binding of radiolabeled mAb 376.96 to human pancreatic ductal adenocarcinoma (PDAC) cells and localization in xenografts in immune-deficient mice and evaluated 212 Pb-labeled 376.96 (212 Pb-376.96) for PDAC therapy.

METHODS: In vitro Scatchard assays assessed the specific binding of 212 Pb-376.96 to human PDAC3 adherent differentiated cells and non-adherent cancer initiating cells (CICs) dissociated from tumorspheres. In vitro clonogenic assays were used to measure the proliferation of adherent PDAC3 cells and CIC-enriched tumorspheres treated with 212 Pb-376.96 or the irrelevant isotype-matched 212 Pb-F3-C25. Mice bearing patient derived pancreatic cancer Panc039 xenografts were i.v. injected with 0.17-0.70 MBq 212 Pb-376.96 or isotype control 212 Pb-F3-C25, and used for biodistribution and tumor growth inhibition studies. Mice bearing orthotopic PDAC3 xenografts were i.v. co-injected with 99m Tc-376.96 and 125 I-F3-C25 and used for biodistribution studies.

RESULTS: 212 Pb-376.96 specifically bound to PDAC3 adherent and dissociated tumorsphere CICs; Kd values averaged 9.0 and 21.7 nM, respectively, with 104 -105  binding sites/cell. 212 Pb-376.96 inhibited the clonogenic survival of PDAC3 cells or CICs dissociated from tumorspheres 3-6 times more effectively than isotype-matched control 212 Pb-F3-C25. Panc039 s.c. tumors showed significantly higher uptake of 212 Pb-376.96 (14.0 ± 2.1% ID/g) compared to 212 Pb-F3-C25 (6.5 ± 0.9% ID/g, p < .001) at 24 h after dosing. Orthotopic PDAC3 tumors showed significantly higher uptake of 99m Tc-376.96 (6.4 ± 1.8% ID/g) compared to 125 I-F3-C25 (3.9 ± 0.9% ID/g, p < .05) at 24 h after dosing. Panc039 tumor growth was significantly inhibited by 212 Pb-376.96 compared to 212 Pb-F3-C25 or non-treated control tumors (p < .05).

CONCLUSION: Our results provide evidence for the efficacy of B7-H3 targeted RIT against preclinical models of pancreatic ductal adenocarcinoma (PDAC) and support future studies with 212 Pb-376.96 in combination with chemotherapy to potentiate efficacy against PDAC.