BIODISTRIBUTION AND TUMOR-LOCALIZATION OF IN-111-LABELED UNMODIFIED AND MODIFIED F(AB')(2) FRAGMENTS OF HUMAN MONOCLONAL IGM-(16.88) IN A NUDE-MOUSE MODEL

Unmodified F(ab')(2) and modified Fab'-BMH-Fab' fragments of human mon oclonal IgM (16.88) were compared for biodistribution and tumor locali zation in nude mice bearing LS-174T human colon carcinoma xenografts. Although both unmodified and modified fragments of IgM cleared rapidly from the blood, the radioactivity retentions for each fragment in liv er and kidney were significantly different. Kidney uptake of the modif ied fragment was about 4-fold lower than kidney uptake of the unmodifi ed fragment. Radioactivity uptake in liver was 2-4-fold higher for the modified fragment. Lower liver and higher kidney uptake of unmodified fragments reflected the labile disulfide linkage of F(ab')(2) in thei r hinge region and the subsequent behavior of the Fab' fragments resul ting from the reduction of the disulfide linkage. Higher liver and low er kidney retention of modified fragments, on the other hand, resulted from the different cleavage mechanism of the stable thioether linkage . Tumor targeting was similar for unmodified and modified fragments at approx. 4% of injected dose per gram. These results indicate that the changes in fragment linkage chemistry may provide different pharmacok inetic patterns in vivo and improve the therapeutic application of rad iolabeled fragments in human patients.