Renal uptake and metabolism of radiopharmaceuticals derived from peptides and proteins

Radiolabeled anti-CD20 antibodies have demonstrated impressive efficacy in the treatment of relapsed non-Hodgkin lymphoma. This encourages the treatment of solid tumor with radiolabeled antibody fragments and peptides. However, both preclinical and clinical studies revealed that persistent localization of radioactivity in the kidney constitutes a major obstacle that compromises therapeutic efficacy. Recent extensive studies show that long residence times of radiolabeled end products from lysosomes are responsible for the renal radioactivity levels. Recent studies have also elucidated the involvement of megalin-cubilin in renal tubular reabsorption of radiolabeled antibody fragments and peptides. In light of these findings, efforts are being made to block tubular reabsorption of radiolabeled antibody fragments and peptides by competitive inhibitors, charge modification, and PEGylation. An interposition of an enzyme-cleavable linkage between antibody fragments and radiolabels would constitute an alternative approach to reduce renal radioactivity levels. Recent findings of these studies will be described.