Noninvasive Imaging of PSMA in prostate tumors with (89)Zr-Labeled huJ591 engineered antibody fragments: the faster alternatives.
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.
Department of Radiology and the Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
Nerissa Therese
NT
Viola-Villegas
Kuntal K
KK
Sevak
Sean D
SD
Carlin
Michael G
MG
Doran
Henry W
HW
Evans
Derek W
DW
Bartlett
Anna M
AM
Wu
Jason S
JS
Lewis
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D000954:Antigens, Surface / Q000276:immunology*; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D007128:Immunoglobulin Fragments; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D057127:Single-Chain Antibodies / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D007128:Immunoglobulin Fragments; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D057127:Single-Chain Antibodies; D015040:Zirconium; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
Cys-diabody; PET; PSMA; huJ591; minibody