IMPROVED TUMOR TARGETING OF TC-99M FAB BY CHEMICAL MODIFICATIONS

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This project was developed and is directed by C.H. Paik, Ph.D. We have been developing chemical methods to radiolabel monoclonal antibodies and their fragments to use as scintigraphic imaging agents to detect hematologic malignancies that express IL-2 receptors. For FY 99 we have extended our efforts to label Fab fragments of anti-Tac monoclonal antibody with Tc-99m using Tc-99m-mercaptoacetyltriglycine as a chelator. The labeled Fab localized in IL-2 receptor-positive ATAC tumors rapidly but cleared rapidly from blood and all organs except kidneys. To improve its pharmacokinetic property with respect to its high renal uptake, we lowered the isoelectric point (pI >9.3) of Fab by acylation of its amino groups with tetrafluorophenyl ester of glycolic acid. This reaction neutralizes one positive charge on an amino group of Fab and at the same time adds one hydroxyl group to Fab. The glycolated Tc-99m-labeled Fab with a pI range of 4.6-6.6 decreased the renal accumulation to 14 percent of that of the control Tc-99m-labeled Fab at 15 min postinjection and increased its peak tumor uptake to 14 percent injected dose per gram (ID/g) from 7 percent ID/g for the control. This study suggests that the renal uptake of Fab involves charge interactions between positively charged Fab and negatively charged phospholipid bilayers of renal parenchymal cell membranes and that the lowering of the pI decreases the renal uptake. The neutralization of the positive charges of Fab by acylation with glycolate molecules and the use of Tc-99m-mercaptoacetyltriglycine for radiolabeling improved the peak tumor uptake value but it reduced the renal uptake.