89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo Journal Article
| Authors: | Holland, J. P.; Divilov, V.; Bander, N. H.; Smith-Jones, P. M.; Larson, S.; Lewis, J. S. |
| Article Title: | 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo |
| Abstract: | 89Zr (half-life, 78.41 h) is a positron-emitting radionuclide that displays excellent potential for use in the design and synthesis of radioimmunoconjugates for immunoPET. In the current study, we report the preparation of 89Zr-desferrioxamine B (DFO)-J591, a novel 89Zr-labeled monoclonal antibody (mAb) construct for targeted immunoPET and quantification of prostate-specific membrane antigen (PSMA) expression in vivo. Methods: The in vivo behavior of 89Zr-chloride, 89Zr-oxalate, and 89Zr-DFO was studied using PET. High-level computational studies using density functional theory calculations have been used to investigate the electronic structure of 89Zr-DFO and probe the nature of the complex in aqueous conditions. 89Zr-DFO- J591 was characterized both in vitro and in vivo. ImmunoPET in male athymic nu/nu mice bearing subcutaneous LNCaP (PSMA-positive) or PC-3 (PSMA-negative) tumors was conducted. The change in 89Zr-DFO-J591 tissue uptake in response to high- and low-specific-activity formulations in the 2 tumor models was measured using acute biodistribution studies and immunoPET. Results: The basic characterization of 3 important reagents-89Zr-chloride, 89Zr-oxalate, and the complex 89Zr-DFO - demonstrated that the nature of the 89Zr species dramatically affects the biodistribution and pharmacokinetics. Density functional theory calculations provide a rationale for the observed high in vivo stability of 89Zr-DFO-labeled mAbs and suggest that in aqueous conditions, 89Zr-DFO forms a thermodynamically stable, 8-coordinate complex by coordination of 2 water molecules. 89Zr-DFO-J591 was produced in high radiochemical yield (>77%) and purity (>99%), with a specific activity of 181.7 ± 1.1 MBq/mg (4.91 ± 0.03 mCi/mg). In vitro assays demonstrated that 89Zr-DFO-J591 had an initial immunoreactive fraction of 0.95 ± 0.03 and remained active for up to 7 d. In vivo biodistribution experiments revealed high, target-specific uptake of 89Zr-DFO-J591 in LNCaP tumors after 24, 48, 96, and 144 h (34.4 ± 3.2 percentage injected dose per gram [%ID/g], 38.0 ± 6.2 %ID/g, 40.4 ± 4.8 %ID/g, and 45.8 ± 3.2 %ID/g, respectively). ImmunoPET studies also showed that 89Zr-DFO-J591 provides excellent image contrast, with tumor-to-muscle ratios greater than 20, for the delineation of LNCaP xenografts between 48 and 144 h after administration. Conclusion: These studies demonstrate that 89Zr-DFO-labeled mAbs show exceptional promise as radiotracers for immunoPET of human cancers. 89Zr-DFO-J591 displays high tumor-to-background tissue contrast in immunoPET and can be used to delineate and quantify PSMA-positive prostate tumors in vivo. Copyright © 2010 by the Society of Nuclear Medicine, Inc. |
| Keywords: | controlled study; unclassified drug; nonhuman; positron emission tomography; radiopharmaceuticals; antigen expression; prostate specific antigen; mouse; animal; animals; mice; animal tissue; animal experiment; animal model; in vivo study; in vitro study; tumor xenograft; immunoreactivity; monoclonal antibodies; monoclonal antibody; prostate-specific antigen; biosynthesis; immunology; monoclonal antibody j591; antibodies, monoclonal; statistical analysis; data interpretation, statistical; immunoglobulin g; diagnostic agent; drug distribution; isotope labeling; xenograft; nude mouse; tissue distribution; mice, nude; positron-emission tomography; radiopharmaceutical agent; transplantation, heterologous; models, molecular; chemical structure; tracer; neoplasm transplantation; density functional theory; drug stability; drug formulation; radiochemistry; cancer transplantation; j591; oxalate zr 89; 89zr; immunopet; prostate-specific membrane antigen (psma); chloride zr 89; desferrioxamine b zr 89; antibody conjugate; immunoconjugates |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 51 |
| Issue: | 8 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2010-08-01 |
| Start Page: | 1293 |
| End Page: | 1300 |
| Language: | English |
| DOI: | 10.2967/jnumed.110.076174 |
| PUBMED: | 20660376 |
| PROVIDER: | scopus |
| PMCID: | PMC2998794 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: JNMEA" - "Source: Scopus" |
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