A Gallium-67/68-Labeled Antibody Fragment for Immuno-SPECT/PET Shows Low Renal Radioactivity Without Loss of Tumor Uptake.
basic_science · Level V
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- Record sourced from PubMed, PMID 29666303.
- Also identified by DOI 10.1158/1078-0432.CCR-18-0123.
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Abstract
<b>Purpose:</b> This study was undertaken to evaluate the renal radioactivity levels of a newly designed <sup>67</sup>Ga-labeled antibody fragment with a linkage cleaved by enzymes present on the brush border membrane (BBM) lining the lumen of the renal tubule.<b>Experimental Design:</b><sup>67</sup>Ga-labeled S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) was conjugated with an antibody Fab fragment through a Met-Val-Lys linkage (<sup>67</sup>Ga-NOTA-MVK-Fab) considering that a Met-Val sequence is a substrate of enzymes on the renal BBM and <sup>67</sup>Ga-NOTA-Met is excreted from the kidney into the urine. The enzymatic recognition of the linkage was evaluated with a low-molecular-weight <sup>67</sup>Ga-NOTA-Met-Val-Lys derivative. Biodistribution of radioactivity after injection of <sup>67</sup>Ga-NOTA-MVK-Fab into mice was compared with <sup>67</sup>Ga-NOTA-conjugated Fab fragments through a Met-Ile linkage that liberates <sup>67</sup>Ga-NOTA-Met (<sup>67</sup>Ga-NOTA-MI-Fab) or a conventional thiourea linkage (<sup>67</sup>Ga-NOTA-Fab).<b>Results:</b> The MVK linkage remained stable in plasma and was recognized by enzymes on renal BBM to liberate <sup>67</sup>Ga-NOTA-Met. When injected into mice, all three <sup>67</sup>Ga-labeled Fab exhibited similar blood clearance rates and tumor accumulation. Significant differences were observed in the kidney where <sup>67</sup>Ga-NOTA-MVK-Fab registered the lowest renal radioactivity levels from early postinjection time (<i>P</i> < 0.05), followed by <sup>67</sup>Ga-NOTA-MI-Fab, which was well reflected in the SPECT/CT images.<b>Conclusions:</b> These findings indicated that our proposal of liberating a radiolabeled compound to urinary excretion from antibody fragments at the renal BBM to reduce the renal radioactivity levels was applicable to <sup>67/68</sup>Ga-labeled antibody fragments. Because antibody fragments and constructs share similar metabolic fates in the kidney, the present labeling procedure would also apply to a variety of antibody fragments and constructs of interest. <i>Clin Cancer Res; 24(14); 3309-16. ©2018 AACR</i>.
Medical subject headings
- Gallium Radioisotopes
- Immunoconjugates
- Immunoglobulin Fab Fragments
- Neoplasms
- Positron-Emission Tomography
- Tomography, Emission-Computed, Single-Photon