Full preclinical validation of the 123I-labeled anti-PSMA antibody fragment ScFvD2B for prostate cancer imaging.

Barbara Frigerio,Ettore Seregni,Elena Luison,Mariangela Figini,Marco Colombatti,Riccardo Valdagni,Otto Boerman,Alessandro Satta,Giulio Fracasso,Silvana Canevari,Delia Mezzanzanica,Gerben Franssen

doi:10.18632/oncotarget.14229

Abstract

PurposeIn the context of prostate cancer (PCa) imaging, the aim of this study was to optimize (in vitro) the specificity and assess preclinically (in vivo) the tumor targeting properties of the 123I-scFvD2B antibody specific for prostate-specific membrane antigen (PSMA).Experimental DesignThe 123I-labeling conditions of the antibody fragment scFvD2B, produced in an eukaryotic system under GMP-compliant conditions, were optimized and assessed for purity and immunoreactivity. The specificity and potency of tumor uptake were tested in three preclinical in vivo models of subcutaneously xenografted human tumors expressing different levels of PSMA (LNCaP, naturally expressing PSMA; PC3-PIP and LS174T-PSMA, transfected with PSMA) or PC3 and LS174T, as negative controls, to assess the clearance, biodistribution and imaging potential of 123I-scFvD2B.ResultsThe set conditions of production and radiolabeling yielded a reagent suitable for human delivery thanks to the purity of the formulation and the high immunoreactivity. In all preclinical models 123I-scFvD2B showed specific targeting only to PSMA-positive tumors with the final specific activity ranging up to 1500 MBq/mg. Despite different levels of PSMA expression, biodistribution analyses and SPECT/CT imaging demonstrated similar results and maximal signal-to-background ratios 24 hours after injection.ConclusionsDue to its in vitro and in vivo properties, 123I-scFvD2B could be a promising tool for the early diagnosis of PCa, and may represent a molecular imaging option to monitor disease progression and assist in the clinical management of PCa patients.

Highlights

Prostate cancer (PCa) is the second most frequently diagnosed cancer among males worldwide [1]
Conventional imaging techniques such as bone scintigraphy, computed tomography (CT), ultrasound, and magnetic resonance imaging are currently used to www.impactjournals.com/oncotarget detect primary PCa and metastatic disease; in order to optimize the management of PCa patients improved imaging modalities are needed
prostatespecific membrane antigen (PSMA) is overexpressed in the malignant epithelial cells that define PCa [4]. 111Inlabeled capromab pendetide (ProstaScint®), an anti-PSMA murine monoclonal antibody [5, 6] conjugated with a derivative of diethylenetriaminepentaacetic acid (DTPA) [7], has been approved for diagnostic imaging by the US Food and Drug Administration but not by the European Medicines Agency, as it has shown some limitations [8]

Summary

Introduction

Prostate cancer (PCa) is the second most frequently diagnosed cancer among males worldwide [1]. Due to its insidious behaviour, early diagnosis of PCa is difficult to diagnose in the early phase of the disease and many patients present with metastatic disease at diagnosis [2] Conventional imaging techniques such as bone scintigraphy, computed tomography (CT), ultrasound, and magnetic resonance imaging are currently used to www.impactjournals.com/oncotarget detect primary PCa and metastatic disease; in order to optimize the management of PCa patients improved imaging modalities are needed. In this scenario, positron emission tomography (PET) and single photon emission computed tomography (SPECT) with emerging radiopharmaceuticals may provide accurate staging of primary disease, restaging of tumor recurrence, and detection of metastatic disease. Many ongoing studies are using radiolabeled small peptides that bind the extracellular domain of PSMA; some of these peptides show good localization, high tracer uptake in the kidneys and salivary glands raised a major concern [9]

Objectives

Methods

Results

Conclusion