Improved renal clearance and tumor targeting of Tc-99m-labeled anti-Tac monoclonal antibody Fab by chemical modifications

초록

This study was undertaken to improve the renal clearance and tumor targeting properties of Tc-99m-labeled humanized anti-Tac (HuTac) monoclonal antibody Fab fragments using two chemical approaches: 1) labeling with a renal secretion agent Tc-99m-mercaptoacetyltrialycine (MAG3) and 2) lowering its isoelectric point (pI) by acylation. HuTac Fab (3.3 mg/mL) was reacted with a trifluorophenyl ester (TFP) of Tc-99m-MAG3 alone or was additionally reacted with TFP-glycolate to reduce the pI. In Balb/c mice, Tc-99m-MAG3-Fab (pI > 9.3) rapidly accumulated in the kidneys (177% injected dose [ID]/g at 15 min) and then gradually cleared out of the kidneys. In contrast, the glycolation (pI 4.6-6.6) drastically reduced the renal uptake (31% ID/g) and also the whole-body retention (82% ID vs 101% for the nonglycolated) at 15 min, indicating that the glycolated Tc-99m-MAG3-Fab (pI 4.6-6.6) was rapidly excreted. The glycolated remained in the blood longer than the nonglycolated (1.2% vs 0.3% ID/g at 360 min), but this effect was less drastic than the effect shown on the renal uptake. In nude mice bearing receptor-positive (ATAC4) tumors, the glycolated (99m)-Tc-MAG3-Fab increased the peak tumor uptake to 14.8% ID/g from 8.3% ID/g for Tc-99m-MAG3-Fab, whereas the glycolation resulted in a drastic reduction of the renal uptake at 15 min. We demonstrated that the renal clearance and the tumor targeting of Fab could be optimized by chemical modifications. (C) 2002 Elsevier Science Inc. All rights reserved.

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