Effect of metabolism on retention of indium-111-labeled monoclonal antibody in liver and blood.

Abstract

The effect of a chelator structure on the metabolic fate of the 111In-labeled monoclonal antibody (Mab) T101 was investigated in normal Balb/c mice to assess the importance of this chemical parameter in the reduction of the background radioactivity in blood and liver. Mab T101 was conjugated with either 2-(p-isothiocyanatobenzyl)-6-methyl-diethylaminetriaminepentaac etic acid (DTPA) (1B4M), 2-(p-isothiocyanatobenzyl) cyclohexyl-DTPA (CHX-B) or cyclic DTPA dianhydride (cDTPA) and then radiolabeled with 111In. Normal mice were injected intravenously with these 111In-labeled T101 conjugates and sacrificed in groups of five up to 5 days postinjection for comparative biodistribution studies and analyses of liver, blood and urine samples for radioindium products. The biodistribution of 111In-1B4M-T101 and 111In-CHX-B-T101 were similar to each other but significantly different from that of 111In-cDTPA-T101, particularly in the blood and liver. Size-exclusion high-performance liquid chromatography indicated that the concentration of the intact 111In-immunoglobulin (Ig)G in liver decreased with similar rates for the three conjugates. Meanwhile, the concentration of a small DTPA-like metabolite in liver increased to a different peak value (4.6% ID/g for the cDTPA conjugate and 1.6% ID/g for the 1B4M and CHX-B conjugates) approximately at 24 hr and maintained a steady-state concentration up to 5 days. The thiourea linkage between T101 and the 111In-labeled chelates and a higher complex stability and higher lipophilicity of 111In-1B4M and 111In-CHX-B appear to be responsible for lower liver and higher blood radioactivity for the 1B4M and CHX-B conjugates.