Pb-labeled B7-H3-targeting Antibody for Pancreatic Cancer Therapy in Mouse Models

Overview

Journal Nucl Med Biol

Publisher Elsevier

Specialties Biology
Nuclear Medicine

Date 2018 Feb 8

PMID 29413459

Citations 32

Authors

Benjamin B Kasten

Abhishek Gangrade

Harrison Kim

Jinda Fan

Soldano Ferrone

Cristina R Ferrone

Kurt R Zinn

Donald J Buchsbaum

Affiliations

Soon will be listed here.

Abstract

Introduction: We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted α-particle radioimmunotherapy (RIT) with 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 Pb-labeled 376.96 (Pb-376.96) for PDAC therapy.

Methods: In vitro Scatchard assays assessed the specific binding of 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 Pb-376.96 or the irrelevant isotype-matched Pb-F3-C25. Mice bearing patient derived pancreatic cancer Panc039 xenografts were i.v. injected with 0.17-0.70 MBq Pb-376.96 or isotype control Pb-F3-C25, and used for biodistribution and tumor growth inhibition studies. Mice bearing orthotopic PDAC3 xenografts were i.v. co-injected with Tc-376.96 and I-F3-C25 and used for biodistribution studies.

Results: Pb-376.96 specifically bound to PDAC3 adherent and dissociated tumorsphere CICs; K values averaged 9.0 and 21.7 nM, respectively, with 10-10 binding sites/cell. Pb-376.96 inhibited the clonogenic survival of PDAC3 cells or CICs dissociated from tumorspheres 3-6 times more effectively than isotype-matched control Pb-F3-C25. Panc039 s.c. tumors showed significantly higher uptake of Pb-376.96 (14.0 ± 2.1% ID/g) compared to Pb-F3-C25 (6.5 ± 0.9% ID/g, p < .001) at 24 h after dosing. Orthotopic PDAC3 tumors showed significantly higher uptake of Tc-376.96 (6.4 ± 1.8% ID/g) compared to I-F3-C25 (3.9 ± 0.9% ID/g, p < .05) at 24 h after dosing. Panc039 tumor growth was significantly inhibited by Pb-376.96 compared to 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 Pb-376.96 in combination with chemotherapy to potentiate efficacy against PDAC.

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