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Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with (177)Lu: in vitro comparison of acyclic and macrocyclic ligands.
- Source :
-
Nuclear medicine and biology [Nucl Med Biol] 2009 Feb; Vol. 36 (2), pp. 117-28. - Publication Year :
- 2009
-
Abstract
- Introduction: The monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor-specific mAb with the low-energy beta-emitter (177)Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized.<br />Materials and Methods: L8A4 mAb was labeled with (177)Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA), 2-(4-isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and alpha-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.DeltaEGFR glioma cells over 24 h to directly compare (177)Lu-labeled L8A4 to L8A4 labeled with (125)I using either iodogen or N-succinimidyl 4-guanidinomethyl-3-[(125)I]iodobenzoate ([(125)I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of (177)Lu to (125)I activity retained in U87.DeltaEGFR cells.<br />Results: All chelates demonstrated higher retention of internalized activity compared with mAb labeled using iodogen, with (177)Lu/(125)I ratios of >20 observed for the three DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for (125)I was higher than (177)Lu from 1-8 h with the opposite behavior observed thereafter. At 24 h, (177)Lu/(125)I ratios were between 1.5 and 3, with higher values observed for the three DTPA chelates.<br />Conclusions: The nature of the chelate used to label this internalizing mAb with (177)Lu influenced intracellular retention in vitro, although at early time points, only MeO-DOTA provided more favorable results than radioiodination of the mAb via SGMIB.
- Subjects :
- Animals
Antibodies, Monoclonal pharmacokinetics
Antibodies, Monoclonal therapeutic use
Brain Neoplasms radiotherapy
Cell Line, Tumor
Chromatography, High Pressure Liquid
Glioma radiotherapy
Ligands
Lutetium pharmacokinetics
Mice
Radioisotopes pharmacokinetics
Radioisotopes therapeutic use
Radiopharmaceuticals pharmacokinetics
Radiopharmaceuticals therapeutic use
Antibodies, Monoclonal chemistry
Chelating Agents chemistry
ErbB Receptors immunology
Isotope Labeling methods
Macrocyclic Compounds chemistry
Radioimmunotherapy
Radioisotopes chemistry
Radiopharmaceuticals chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0969-8051
- Volume :
- 36
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Nuclear medicine and biology
- Publication Type :
- Academic Journal
- Accession number :
- 19217523
- Full Text :
- https://doi.org/10.1016/j.nucmedbio.2008.11.001