DISCRIMINATED RELEASE OF A HIPPURATE-LIKE RADIOMETAL CHELATE IN NONTARGET TISSUES FOR TARGET-SELECTIVE RADIOACTIVITY LOCALIZATION USING PH-DEPENDENT DISSOCIATION OF REDUCED ANTIBODY

To achieve high and selective target radioactivity localization by mon oclonal antibodies (Mabs) labeled with metallic radionuclides, the dis criminated release of a hippurate-like radiometal chelate in nontarget tissues was performed using chemically modified Mabs. Methods: The di sulfide bonds of a Mab against osteogenic sarcoma (OST7, IgG(1)) were reduced and Ga-67 chelate of succinyldeferoxamine (SDF) was conjugated proximal to the Mab molecule via an ester bond with exposed thiol gro ups (Ga-67-DFO-MESS-redOST7), which would impair esterase access to th e ester bond of Ga-67-DFO-MESS-redOST7 due to the steric interference induced by bulky antibody molecule, stabilizing the ester bond in plas ma and on the target cell's surface, Gallium-67-SDF was also conjugate d to OST7 via an ester bond with 2-iminothiolane to render the ester b ond in a position distal from the OST7 molecule (Ga-67-DFO-MESS-IT-OST 7). Results: Although SDS-PAGE analyses of Ga-67-DFO-MESS-redOST7 show ed a partial cleavage of its disulfide bonds, size-exclusion HPLC and cell binding assays indicated that the IgG structure and immunoreactiv ity of this conjugate were preserved in a neutral buffer and plasma of the systemic circulation. Conclusion: The present radiochemical desig n of an antibody utilizing pH-dependent dissociation would constitute a promising approach in establishing selective target radioactivity lo calization by Mabs.