A new bifunctional chelate, BrMe2HBED: An effective conjugate for radiometals and antibodies

A new bifunctional chelate, N-(2-hydroxy-3,5-dimethylbenzyl)-N'-(2-hydroxy-5-(bromoacetamido)benzyl)ethylenediamine-N,-N'-diacetic acid (BrMe2HBED), was designed and synthesized to bind trivalent cationic metals with monoclonal antibodies. The stability constants (log values) for indium complexed with a similar ligand, HBED, were increased over those of more commonly used ligands DTPA and EDTA. Predictably, the increased metal-ligand complex stability would expedite the in vivo clearance from nontarget regions and perhaps enhance the localization of the radiolabeled antibody (Ab). BrMe2HBED was conjugated with the Ab (24 h) and then radiolabeled with indium-111 citrate (24 h). Additionally, the Ab was radiolabeled by using conventional methods (111In-DTPA and 125I-lactoperoxidase) and then compared by measuring the in vitro stability, in vitro immunoreactivity(IR), and in vivo distribution and clearance. A 10:1 BrMe2 HBED:Ab mole ratio resulted in good labeling efficiency with 111In and more importantly a very high IR. In a hamster tumor model, 111In-BrMe2 HBED-labeled monoclonal antibody (1A3) had high uptake in the tumor tissue and preferable blood clearance compared to either of the more conventional radiolabeled 1A3 monoclonal antibodies (111In-DTPA or 125I-lactoperoxidase). 49 refs., 4 figs., 8 tabs