title: In vitro evaluation of two polyhedral boron anion derivatives as linkers for attachment of radioiodine to the anti-HER2 monoclonal antibody trastuzumab.
abstract: Improving intracellular retention is important for the use of radiohalogens in radionuclide therapy using internalizing antibodies. Two putative linkers for residualization of radioiodine labels, 7-(4-isothiocyanato-phenyl)undecahydro-7,8-dicarba-nido-undecaborate(1-) ion (NBI) and (4-isothiocyanato-benzylammonio)undecahydro-closo-dodecaborate(1-) (DABI), were analyzed. The anti-HER-2 antibody, trastuzumab, was labeled with iodine-125 using NBI and DABI linkers, and, for comparison, with the para-[(125)I]iodobenzoate (PIB), and Chloramine-T((R)) (CAT) methods. The different labels were tested for residualizing properties using the HER-2 overexpressing SKBR-3 cells. The cellular radioactivity retention showed that DABI provided a 55% better retention than CAT and was 42% better than PIB after 20 hours. NBI did not improve retention. Accumulation tests up to 21 hours showed that the HER-2-specific accumulation of radioactivity delivered with DABI was, on average, 33% higher than with the use of PIB. These DABI-dependent improvements could, with high probability, be attributed to the good residualizing properties of DABI. The affinity of DABI-labeled trastuzumab to SKBR-3 cells was not better than the affinity of the PIB labeled (3.2 +/- 1.9 nM and 0.77 +/- 0.39 nM, respectively). In conclusion, the use of the DABI linker improved intracellular retention in vitro in comparison with the other labeling methods.
authors.affiliation: Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Persson
authors.forename: Igor
authors.initials: I
authors.lastname: Sivaev
authors.forename: Karl Johan
authors.initials: KJ
authors.lastname: Winberg
authors.forename: Lars
authors.initials: L
authors.lastname: Gedda
authors.forename: Per-Uno
authors.initials: PU
authors.lastname: Malmström
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000915:Antibody Affinity / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001896:Boron Compounds / Q000737:chemistry*; D045744:Cell Line, Tumor; D002700:Chloramines / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry*; D005260:Female; D054879:Halogenation; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D007463:Iodobenzoates / Q000737:chemistry; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution; D014105:Tosyl Compounds / Q000737:chemistry; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001896:Boron Compounds; D002700:Chloramines; D003432:Cross-Linking Reagents; D007457:Iodine Radioisotopes; D007463:Iodobenzoates; D009942:Organometallic Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D014105:Tosyl Compounds; D000068878:Trastuzumab; C016300:chloramine-T; C510145:potassium (125I)-(4-isothiocyanatobenzylammonio)iodo-decahydro-closo-dodecaborate