A newly designed radioimmuno-conjugate releasing a hippurate-like radiometal chelate for enhanced target/non-target radioactivity

Target-to-non-target ratio of radioactivity can be enhanced by the injection of monoclonal antibodies (MoAbs) labeled with metallic radionuclides, if some modality to accelerate the urinary excretion of radioactivity accumulated in non-target tissues could be introduced. In this study, a radioimmunoconjugate chemically designed to release a hippurate-like radiometal chelate was synthesized and tested in vivo. A 67Ga chelate of succinyldeferoxamine (SDF) was conjugated with a MoAb against osteogenic sarcoma (OST7, IgG1) through an ester bond using a new metabolizable MESS linker, N-[I4-(maleimidoethoxy)succinyl]oxy]succinimide (67Ga-DFO-MESS-OST7). When injected into normal mice, 67Ga-DFO-MESS-OST7 exhibited faster clearance of radioactivity from circulation with less accumulation in the liver, kidney and spleen than those observed with 67Ga-DFO-EMCS-OST7, which was prepared under identical conditions to 67Ga-DFO-MESS-OST7 except for using a non-metabolizable linker holding no ester bond to release 67Ga-SDF. Size exclusion HPLC analysis of the liver homogenate obtained from mice 24 h after injection of 67Ga-DFO-MESS-OST7 indicated that all the radioactivity was eluted in the high molecular weight fraction with most of it being present as the 67Ga-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 67Ga-SDF. In athymic mice bearing osteogenic sarcoma, 67Ga-DFO-MESS-OST7 exhibited higher tumor-to-blood and tumor-to-organ ratio of radioactivity when compared with 67Ga-DFO-EMCS-OST7. These results indicated that 67Ga-DFO-MESS-OST7 achieved enhanced target-to-non-target ratio of the radioactivity, due to preferential cleavage of the ester bond in non-target tissues, followed by rapid urinary excretion of the resulting chelate (probably as 57Ga-SDF). These results also suggest that the present design would become an applicable modality for enhancing the target-to-non-target ratio of radioactivity by MoAbs.