title: Discriminated release of a hippurate-like radiometal chelate in nontarget tissues for target-selective radioactivity localization using pH-dependent dissociation of reduced antibody.
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.
  
  
  CONCLUSIONS
  The present radiochemical design of an antibody utilizing pH-dependent dissociation would constitute a promising approach in establishing selective target radioactivity localization by Mabs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Arano
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Mukai
authors.forename: K
authors.initials: K
authors.lastname: Wakisaka
authors.forename: H
authors.initials: H
authors.lastname: Sakahara
authors.forename: J
authors.initials: J
authors.lastname: Konishi
authors.forename: A
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D005710:Gallium Radioisotopes; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D012516:Osteosarcoma / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D016719:Radioimmunodetection / Q000379:methods*; D016499:Radioimmunotherapy / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D005710:Gallium Radioisotopes