The in vivo fate of various 111In-labeled polypeptides has been the subject of many investigations. Intracellular metabolism has been studied through the use of 111In-labeled glycoproteins that are concentrated in the lysosome by receptor-mediated endocytosis. These studies have indicated that the main lysosomal metabolite is 111In-chelate-ε-lysine, both in vitro and in vivo (Y. Arano et al., J. Nucl. Med., 35: 890–898, 1994; F. N. Franano et al., Nucl. Med. Biol., 21: 1023–1034, 1994). Since the vast majority of radiolabeled antibodies do not localize within the target tissue, an understanding of the metabolism of 111In-labeled antibodies in nontarget tissues is important for the rational design of future radiolabeled antibodies.

We investigated the in vivo metabolism of 111In-DTPA3-conjugated antibody in female Sprague-Dawley rats using the anticolorectal carcinoma monoclonal antibody (MAb) 1A3 and MAb 1A3-F(ab′)2. Livers and kidneys were harvested from rats injected with either intact MAb or MAb fragments and analyzed by gel filtration chromatography. Thirty-five % of the radioactivity from 111In-DTPA-1A3 MAb present in the liver was in the form of a low molecular weight species at 1 through 5 days. In contrast, 111In-DTPA-1A3-F(ab′)2 was >98% degraded to a low molecular weight species in the kidney after 1 day. In each case, the low molecular weight metabolites were collected and further analyzed by silica gel thin-layer chromatography, reversed phase high-performance liquid chromatography, and ion-exchange chromatography and compared to 111In-DTPA and 111In-DTPA-ε-lysine standards. In each system, the major metabolite co-eluted with 111In-DTPA-ε-lysine, similar to the results obtained with 111In-labeled glycoproteins that are delivered to lysosomes by receptor-mediated endocytosis. A minor metabolite that was more highly charged than 111In-DTPA was also observed. Analysis of urine and feces demonstrated that the main excretory product of both 111In-labeled intact 1A3 and 1A3-F(ab′)2 was 111In-DTPA-ε-lysine. Based on this data, we propose that 111In-DTPA-antibodies are degraded within lysosomes of nontarget organs such as the liver and kidneys.


Presented at the “Fifth Conference on Radioimmunodetection and Radioimmunotherapy of Cancer,” October 6–8, 1994, Princeton, NJ. This work was funded by Department of Energy Grant DE-FG02-87ER-60512 (to M. J. W.) and the NIH (Grant CA-42925) with the National Cancer Institute (to M. J. W.).

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