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摘要
Purpose: This study was undertaken to evaluate the renal radioactivity levels of a newly designed Ga-67-labeled antibody fragment with a linkage cleaved by enzymes present on the brush border membrane (BBM) lining the lumen of the renal tubule.
Experimental Design: Ga-67-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 (Ga-67-NOTA-MVK-Fab) considering that a Met-Val sequence is a substrate of enzymes on the renal BBM and Ga-67-NOTA-Met is excreted from the kidney into the urine. The enzymatic recognition of the linkage was evaluated with a low-molecular-weight Ga-67-NOTA-Met-Val-Lys derivative. Biodistribution of radioactivity after injection of Ga-67-NOTA-MVK-Fab into mice was compared with Ga-67-NOTA-conjugated Fab fragments through a Met-Ile linkage that liberates Ga-67-NOTA-Met (Ga-67-NOTA-MI-Fab) or a conventional thiourea linkage (Ga-67-NOTA-Fab).
Results: The MVK linkage remained stable in plasma and was recognized by enzymes on renal BBM to liberate Ga-67-NOTA-Met. When injected into mice, all three Ga-67-labeled Fab exhibited similar blood clearance rates and tumor accumulation. Significant differences were observed in the kidney where Ga-67-NOTA-MVK-Fab registered the lowest renal radioactivity levels from early postinjection time (P < 0.05), followed by Ga-67-NOTA-MI-Fab, which was well reflected in the SPECT/CT images.
Conclusions: 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 Ga-67/68-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.
- 出版日期2018-7-15
