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Discriminated Release of a Hippurate-Like Radiometal Chelate in Nontarget Tissues for Target-Selective Radioactivity Localization Using pH-Dependent Dissociation of Reduced Antibody

Faculty of Pharmaceutical Sciences and Faculty of Medicine, Kyoto University, Kyoto, Japan

Correspondence: For correspondence and reprints contact: Akira Yokoyama, PhD, Dept. of Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606 Japan.

ABSTRACT

To achieve high and selective target radioactivity localization by monoclonal antibodies (Mabs) labeled with metallic radionuclides, the discriminated release of a hippurate-like radiometal chelate in nontarget tissues was performed using chemically modified Mabs. Methods: The disulfide bonds of a Mab against osteogenic sarcoma (OST7, IgG₁) were reduced and ⁶⁷Ga chelate of succinyldeferoxamine (SDF) was conjugated proximal to the Mab molecule via an ester bond with exposed thiol groups (⁶⁷Ga-DFO-MESS-redOST7), which would impair esterase access to the ester bond of ⁶⁷Ga-DFO-MESS-redOST7 due to the steric interference induced by bulky antibody molecule, stabilizing the ester bond in plasma and on the target cell's surface. Gallium-67-SDF was also conjugated to OST7 via an ester bond with 2-iminothiolane to render the ester bond in a position distal from the OST7 molecule (⁶⁷Ga-DFO-MESS-IT-OST7). Results: Although SDS-PAGE analyses of ⁶⁷Ga-DFO-MESS-redOST7 showed a partial cleavage of its disulfide bonds, size-exclusion HPLC and cell binding assays indicated that the IgG structure and immunoreactivity of this conjugate were preserved in a neutral buffer and plasma of the systemic circulation. Conclusion: The present radiochemical design of an antibody utilizing pH-dependent dissociation would constitute a promising approach in establishing selective target radioactivity localization by Mabs.

Key Words: gallium-67 • monoclonal antibodies • target selection

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