title: Effect of radiochemical modification on biodistribution of scFvD2B antibody fragment recognising prostate specific membrane antigen.
abstract: Antibody-based reagents represent a promising strategy as clinical diagnostic tools. Prostate cancer (PCa) is the second-leading cause of death in males in the Western population. There is a presently unmet need for accurate diagnostic tool to localize and define the extent of both primary PCa and occult recurrent disease. One of the most suitable targets for PCa is the prostate-specific membrane antigen (PSMA) recognised by the monoclonal antibody D2B that we re-shaped into the single chain Fv (scFv format). Aim of this study was to evaluate in preclinical in vivo models the target specificity of scFvD2B after labelling with different radionuclides. (111)In radiolabelling was performed via the chelator Bz-NOTA, and (131)I radioiodination was performed using iodogen. The potential for molecular imaging and the biological behaviour of the radiolabelled scFvD2B were evaluated in mice bearing two subcutaneous PCa isogenic cell lines that differed only in PSMA expression. Biodistribution studies were performed at 3, 9, 15 and 24h after injection to determine the optimal imaging time point. A significant kidney accumulation, as percentage of injected dose of tissue (%ID/g), was observed for (111)In-scFvD2B at 3h after injection (45%ID/g) and it was maintained up to 24h (26%ID/g). By contrast, kidney accumulation of (131)I-scFvD2B was only marginally (0.3%ID/g at 24h). At the optimal time point defined between 15h and 24h, regardless of the radionuclide used, the scFvD2B was able to localize significantly better in the PSMA expressing tumours compared to the negative control; with (131)I-scFvD2B yielding a significantly better target/background ratio compared to (111)In-scFvD2B. These data suggest that, besides antigen specificity, chemical modification may affect antibody fragment biodistribution.
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Frigerio
authors.affiliation: Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benigni
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Luison
authors.affiliation: S.C. Nuclear Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Seregni
authors.affiliation: S.C. Nuclear Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pascali
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Fracasso
authors.affiliation: Prostate Cancer Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Morlino
authors.affiliation: Prostate Cancer Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Valdagni
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: mariangela.figini@istitutotumori.mi.it.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Figini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics; D000918:Antibody Specificity / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019275:Radiopharmaceuticals / Q000276:immunology* / Q000493:pharmacokinetics; D057127:Single-Chain Antibodies / Q000276:immunology* / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D057127:Single-Chain Antibodies; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: Antibody fragments single chain Fv; Prostate cancer imaging; Prostate specific membrane antigen; Radiolabelling