Reduction of the Renal Radioactivity of <sup>111</sup>In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes
Hiroyuki Suzuki, Mari Araki, Kouki Tatsugi, Kento Ichinohe, Tomoya Uehara, Yasushi Arano
Abstract
High Resolution Image Download MS PowerPoint Slide The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular design to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-based reagents for radiotheranostic applications with trivalent radiometals. DOTA or a derivative thereof was conjugated to a Fab through an FGK linkage ([ 111 In]In-DO3A i Bu-Bn-FGK-Fab or [ 111 In]In-DOTA-Bn-FGK-Fab). When injected into mice, both generated radiometabolites, [ 111 In]In-DO3A i Bu-Bn-F and [ 111 In]In-DOTA-Bn-F, by the angiotensin-converting enzyme at similar rates. Both exhibited significantly lower renal radioactivity levels than a 111 In-labeled Fab prepared by the conventional procedure ([ 111 In]In-DOTA-Bn-SCN-Fab). The different elimination rates of each radiometabolite from the kidney significantly affected the renal radioactivity levels. [ 111 In]In-DO3A i Bu-Bn-FGK-Fab preferentially reduced the renal localization without impairing tumor accumulation. These findings would pave the way for developing a DOTA-based radiotheranostic platform for LMW Abs bearing cleavable linkers for renal brush border enzymes.