In Vitro Evaluation of Two Polyhedral Boron Anion Derivatives as Linkers for Attachment of Radioiodine to the Anti-HER2 Monoclonal Antibody Trastuzumab

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-[¹²⁵I]iodobenzoate (PIB), and Chloramine-T^® (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.