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

ABSTRACT: INTRODUCTION:We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted ?-particle radioimmunotherapy (RIT) with 212Pb 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 212Pb-labeled 376.96 (212Pb-376.96) for PDAC therapy. METHODS:In vitro Scatchard assays assessed the specific binding of 212Pb-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 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25. Mice bearing patient derived pancreatic cancer Panc039 xenografts were i.v. injected with 0.17-0.70?MBq 212Pb-376.96 or isotype control 212Pb-F3-C25, and used for biodistribution and tumor growth inhibition studies. Mice bearing orthotopic PDAC3 xenografts were i.v. co-injected with 99mTc-376.96 and 125I-F3-C25 and used for biodistribution studies. RESULTS:212Pb-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. 212Pb-376.96 inhibited the clonogenic survival of PDAC3 cells or CICs dissociated from tumorspheres 3-6 times more effectively than isotype-matched control 212Pb-F3-C25. Panc039 s.c. tumors showed significantly higher uptake of 212Pb-376.96 (14.0?±?2.1% ID/g) compared to 212Pb-F3-C25 (6.5?±?0.9% ID/g, p?

SUBMITTER: Kasten BB 

PROVIDER: S-EPMC5817013 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature