title: An anti-PSMA bivalent immunotoxin exhibits specificity and efficacy for prostate cancer imaging and therapy.
abstract: Prostate specific membrane antigen (PSMA) is overexpressed on prostate tumor cells and the neovascular endothelia various solid tumors. A bivalent immunotoxin generated by fusing a fold-back single-chain diabody derived from the Fv fragments of an anti-PSMA monoclonal antibody with a truncated diphtheria toxin (DT) containing the activity and translocation domains [A-dmDT390-scfbDb(PSMA)] might be suitable for targeted therapy of tumors that overexpress PSMA. In this study, a PSMA-positive and a PSMA-negative prostate cancer cell lines were treated with immunotoxin A-dmDT390-scfbDb(PSMA) in order to study the tumor targeting specificity and therapeutic potential of the immunotoxin. The cellular uptake and selective toxicity of the immunotoxin were evident in monolayer cultures of PSMA-positive LNCaP prostate cancer cells but not in cultures of PSMA-negative PC-3 prostate cancer cells. Cellular accumulation of A-dmDT390-scfbDb(PSMA) increased with increasing incubation times and concentrations in LNCaP cells. The proportion of apoptotic LNCaP cells increased upon incubation with increasing doses of the fold-back immunotoxin. Optical imaging and MRI with the Alexa Fluor 680-labeled A-dmDT390-scfbDb(PSMA) confirmed the specific targeting and therapeutic efficacy of this immunotoxin towards PSMA-positive LNCaP solid tumor xenografts in athymic nude mice.
authors.affiliation: Molecular Imaging Laboratory, Department of Radiology, Howard University, Washington, DC 20060, USA.
authors.forename: Fayun
authors.initials: F
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Shan
authors.forename: Yuanyi
authors.initials: Y
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Neville
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Woo
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.forename: Alexandru
authors.initials: A
authors.lastname: Korotcov
authors.forename: Stephen
authors.initials: S
authors.lastname: Lin
authors.forename: Sophia
authors.initials: S
authors.lastname: Huang
authors.forename: Rajagopalan
authors.initials: R
authors.lastname: Sridhar
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.forename: Paul C
authors.initials: PC
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D005456:Fluorescent Dyes; D006801:Humans; D000922:Immunotoxins / Q000276:immunology* / Q000627:therapeutic use*; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods*; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology
chemical_list: D005456:Fluorescent Dyes; D000922:Immunotoxins; D017430:Prostate-Specific Antigen