A NEWLY DESIGNED RADIOIMMUNOCONJUGATE RELEASING A HIPPURATE-LIKE RADIOMETAL CHELATE FOR ENHANCED TARGET NON-TARGET RADIOACTIVITY/

Target-to-non-target ratio of radioactivity can be enhanced by the inj ection of monoclonal antibodies (MoAbs) labeled with metallic radionuc lides, if some modality to accelerate the urinary excretion of radioac tivity accumulated in non-target tissues could be introduced. In this study, a radioimmunoconjugate chemically designed to release a hippura te-like radiometal chelate was synthesized and tested in vivo. A Ga-67 chelate of succinyldeferoxamine (SDF) was conjugated with a MoAb agai nst osteogenic sarcoma (OST7, IgG(1)) through an ester bond using a ne w metabolizable MESS linker, N-[[4-(maleimidoethoxy)succinyl]oxy]succi nimide (Ga-67-DFO-MESS-OST7). When injected into normal mice, Ga-67-DF OMESS-OST7 exhibited faster clearance of radioactivity from circulatio n with less accumulation in the liver, kidney and spleen than those ob served with Ga-67-DFO-EMCS-OST7, which was prepared under identical co nditions to Ga-67-DFO-MESS-OST7 except for using a non-metabolizable l inker holding no ester bond to release (GaSDF)-Ga-67. Size exclusion H PLC analysis of the liver homogenate obtained from mice 24 h after inj ection of Ga-67-DFO-MESS-OST7 indicated that all the radioactivity was eluted in the high molecular weight fraction with most of it being pr esent as the Ga-67-DFO-MESS-OST7 fraction. Reverse-phase HPLC analysis of urine sample from the same mice showed a single radioactivity peak at the same retention time as that of Ga-67-SDF. In athymic mice bear ing osteogenic sarcoma, Ga-67-DFOMESS-OST7 exhibited higher tumor-to-b lood and tumor-to-organ ratio of radioactivity when compared with Ga-6 7-DFO-EMCS-OST7. These results indicated that Ga-67-DFO-MESS-OST7 achi eved enhanced target-to-non-target ratio of the radioactivity, due to preferential cleavage of the ester bond in non-target tissues, followe d by rapid urinary excretion of the resulting chelate (probably as Ga- 67-SDF). These results also suggest that the present design would beco me an applicable modality for enhancing the target-to-nontarget ratio of radioactivity by MoAbs.