Metabolism and Renal Clearance of 111In-Labeled DOTA-Conjugated Antibody Fragments
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- 作者：S. W. Tsai ; L. Li ; L. E. Williams ; A.-L. Anderson ; A. A. Raubitschek ; and J. E. Shively
- 刊名：Bioconjugate Chemistry
- 出版年：2001
- 出版时间：March 2001
- 年：2001
- 卷：12
- 期：2
- 页码：264 - 270
- 全文大小：129K
- 年卷期：v.12,no.2(March 2001)
- ISSN：1520-4812
文摘
Radiometal-labeled antibody fragments are promising reagents for radioimmunotherapy due to theirhigh tumor uptake and rapid pharmacokinetics, but their therapeutic potentials are limited by highuptake and retention in the kidney. Identification of metabolic products is a first step in designingrationale approaches to lower kidney uptake. Previous studies in rats have shown that 111In-labeledDTPA-conjugated antibody fragments (via lysine residues) were degraded to an DTPA-
-amino-lysinederivative and retained in the lysosomal compartments of the liver and kidney [Rogers et al. (1995)Cancer Res. 55, 5714s-5720s]. To determine the metabolic profile of another widely used metal-chelate,[111In]DOTA conjugated to lysines in antibody fragments via active ester chemistry, we analyzed kidneyhomogenates from nude mice injected with an [111In]DOTA-Fab generated enzymatically from theanti-lymphoma intact antibody Rituxan. The major kidney metabolite was identified as [111In]DOTA--amino-lysine by comparison to an authentic synthetic standard. This end product was also identifiedin the urine, along with relatively small amounts of [111In]DOTA-Fab. Since injection of [111In]DOTA--amino-lysine into nude mice resulted in rapid clearance into the urine without kidney retention, itis likely that the renal retention observed was due to kidney uptake of [111In]DOTA-Fab, followed bylysosomal degradation to [111In]DOTA--amino-lysine, which is only slowly cleared from this compartment. This observation is supported by autoradiographs of the kidney showing rapid localization ofradioactivity into the distal regions of the kidney cortex. To extend this analysis to clinical trials, wehave also analyzed urine taken from a patient injected with the intact antibody [111In]DOTA-cT84.66.In that example, we found that the major radioactive species was also [111In]DOTA--amino-lysine.
-amino-lysinederivative and retained in the lysosomal compartments of the liver and kidney [Rogers et al. (1995)Cancer Res. 55, 5714s-5720s]. To determine the metabolic profile of another widely used metal-chelate,[111In]DOTA conjugated to lysines in antibody fragments via active ester chemistry, we analyzed kidneyhomogenates from nude mice injected with an [111In]DOTA-Fab generated enzymatically from theanti-lymphoma intact antibody Rituxan. The major kidney metabolite was identified as [111In]DOTA--amino-lysine by comparison to an authentic synthetic standard. This end product was also identifiedin the urine, along with relatively small amounts of [111In]DOTA-Fab. Since injection of [111In]DOTA--amino-lysine into nude mice resulted in rapid clearance into the urine without kidney retention, itis likely that the renal retention observed was due to kidney uptake of [111In]DOTA-Fab, followed bylysosomal degradation to [111In]DOTA--amino-lysine, which is only slowly cleared from this compartment. This observation is supported by autoradiographs of the kidney showing rapid localization ofradioactivity into the distal regions of the kidney cortex. To extend this analysis to clinical trials, wehave also analyzed urine taken from a patient injected with the intact antibody [111In]DOTA-cT84.66.In that example, we found that the major radioactive species was also [111In]DOTA--amino-lysine.