Noninvasive Imaging of PSMA in prostate tumors with (89)Zr-Labeled huJ591 engineered antibody fragments: the faster alternatives

• Published in: Molecular pharmaceutics 2014-11, Vol.11 (11), p.3965
• Main Authors: Viola-Villegas, Nerissa Therese, Sevak, Kuntal K, Carlin, Sean D, Doran, Michael G, Evans, Henry W, Bartlett, Derek W, Wu, Anna M, Lewis, Jason S
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacokinetics; Antigens, Surface - immunology; Glutamate Carboxypeptidase II - immunology; Humans; Immunoglobulin Fragments; Iodine Radioisotopes - pharmacokinetics; Male; Mice; Molecular Imaging - methods; Positron-Emission Tomography - methods; Prostatic Neoplasms - diagnostic imaging; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Radiopharmaceuticals - pharmacokinetics; Single-Chain Antibodies - pharmacokinetics; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zirconium - pharmacokinetics
• ISSN: 1543-8392
• DOI: 10.1021/mp500164r

Engineered antibody fragments offer faster delivery with retained tumor specificity and rapid clearance from nontumor tissues. Here, we demonstrate that positron emission tomography (PET) based detection of prostate specific membrane antigen (PSMA) in prostatic tumor models using engineered bivalent antibodies built on single chain fragments (scFv) derived from the intact antibody, huJ591, offers similar tumor delineating properties but with the advantage of rapid targeting and imaging. (89)Zr-radiolabeled huJ591 scFv (dimeric scFv-CH3; (89)Zr-Mb) and cysteine diabodies (dimeric scFv; (89)Zr-Cys-Db) demonstrated internalization and similar Kds (∼2 nM) compared to (89)Zr-huJ591 in PSMA(+) cells. Tissue distribution assays established the specificities of both (89)Zr-Mb and (89)Zr-Cys-Db for PSMA(+) xenografts (6.2 ± 2.5% ID/g and 10.2 ± 3.4% ID/g at 12 h p.i. respectively), while minimal accumulation in PSMA(-) tumors was observed. From the PET images, (89)Zr-Mb and (89)Zr-Cys-Db exhibited faster blood clearance than the parent huJ591 while tumor-to-muscle ratios for all probes show comparable values across all time points. Ex vivo autoradiography and histology assessed the distribution of the probes within the tumor. Imaging PSMA-expressing prostate tumors with smaller antibody fragments offers rapid tumor accumulation and accelerated clearance; hence, shortened wait periods between tracer administration and high-contrast tumor imaging and lower dose-related toxicity are potentially realized.