212Pb-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 alpha-particle radioimmunotherapy (RIT) with Pb-212 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 Pb-212-labeled 376.96 (Pb-212-376.96) for PDAC therapy. Methods: In vitro Scatchard assays assessed the specific binding of Pb-212-376.96 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 Pb-212-376.96 or the irrelevant isotype-matched Pb-212-F3-C25. Mice bearing patient derived pancreatic cancer Panc039 xenografts were iv. injected with 0.17-0.70 MBq Pb-212-376.96 or isotype control Pb-212-F3-C25, and used for biodistribution and tumor growth inhibition studies. Mice bearing orthotopic PDAC3 xenografts were iv. co-injected with Tc-99m-376.96 and I-125-F3-C25 and used for biodistribution studies. Results: Pb-212-376.96 specifically bound to PDAC3 adherent and dissociated tumorsphere CICs; K-d values averaged 9.0 and 21.7 nM, respectively, with 10(4)-10(5) binding sites/cell. Pb-212-376.96 inhibited the clonogenic survival of PDAC3 cells or CICs dissociated from tumorspheres 3-6 times more effectively than isotype-matched control Pb-212-F3-C25. Panc039 s.c. tumors showed significantly higher uptake of Pb-212-376.96 (14.0 +/- 2.1% ID/g) compared to Pb-212-F3-C25 (6.5 +/- 0.9% ID/g, p < .001) at 24 h after dosing. Orthotopic PDAC3 tumors showed significantly higher uptake of Tc-99m-376.96 (6.4 +/- 1.8% ID/g) compared to I-125-F3-C25 (3.9 +/- 0.9% ID/g, p < .05) at 24 h after dosing. Panc039 tumor growth was significantly inhibited by Pb-212-376.96 compared to Pb-212-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 Pb-212-376.96 in combination with chemotherapy to potentiate efficacy against PDAC. (C) 2017 Elsevier Inc. All rights reserved.