Biodistribution and tumor localization of 111In-labeled unmodified and modified F(ab')2 fragments of human monoclonal IgM (16.88) in a nude mouse model.
Unmodified F(ab')2 and modified Fab'-BMH-Fab' fragments of human monoclonal IgM (16.88) were compared for biodistribution and tumor localization in nude mice bearing LS-174T human colon carcinoma xenografts. Although both unmodified and modified fragments of IgM cleared rapidly from the blood, the radioactivity retentions for each fragment in liver and kidney were significantly different. Kidney uptake of the modified fragment was about 4-fold lower than kidney uptake of the unmodified fragment. Radioactivity uptake in liver was 2-4-fold higher for the modified fragment. Lower liver and higher kidney uptake of unmodified fragments reflected the labile disulfide linkage of F(ab')2 in their hinge region and the subsequent behavior of the Fab' fragments resulting from the reduction of the disulfide linkage. Higher liver and lower kidney retention of modified fragments, on the other hand, resulted from the different cleavage mechanism of the stable thioether linkage. Tumor targeting was similar for unmodified and modified fragments at approx. 4% of injected dose per gram. These results indicate that the changes in fragment linkage chemistry may provide different pharmacokinetic patterns in vivo and improve the therapeutic application of radiolabeled fragments in human patients.
Quadri
S M
SM
Department of Experimental Radiotherapy, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Siddiqui
A
A
Klein
J L
JL
Vriesendorp
H M
HM
D000818:Animals; D000911:Antibodies, Monoclonal; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011877:Radionuclide Imaging; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D007205:Indium Radioisotopes