腫瘍選択的な放射能送達を目的とする RI 標識抗腫瘍抗体フラグメントの分子設計―腎刷子縁膜酵素の作用を利用した腎臓への放射能集積の低減―

抄録

Nonspecific renal radioactivity localization constitutes a problem in targeted imaging and therapy with radiolabeled antibody fragments. Based on the idea that the renal radioactivity levels should be reduced if radiolabeled compounds excreted in the urine are released from antibody fragments by tubular brush border enzymes, 3′-iodohippuryl N^ε-maleoyl-L-lysine (HML) was designed as a radioiodination reagent for antibody fragments; the glycyl-lysine sequence in HML is a substrate for a brush border enzyme and m-iodohippuric acid is released by cleavage of the linkage. In normal mice, HML-conjugated Fab demonstrated low renal radioactivity levels from early postinjection times. Directly radioiodinated Fab showed migration of radioactivity from the membrane to the lysosomal fraction of the renal cells from 10 to 30min postinjection. On the other hand, the majority of the radioactivity was detected only in the membrane fraction after injection of HML-conjugated Fab. In tumor-bearing mice, HML-conjugated Fab showed a marked decrease in renal radioactivity localization without impairing the tumor accumulation. These findings indicate that HML is a useful reagent for reducing the renal radioactivity levels of antibody fragments.