Biodistribution and radiation dose estimates for yttrium- and iodine-labeled monoclonal antibody IgG and fragments in nude mice bearing human colonic tumor xenografts.
An anti-carcinoembryonic antigen murine monoclonal antibody designated NP-4, and its F(ab')2 and Fab' fragments, were coupled to the 1/1 mixture of 1-isothiocyanato-benzyl-3-methyl- and 1-methyl-3-isothiocyanato-benzyl-diethylenetriaminepentaacetic acid chelate and labeled with 111In or 88Y. Biodistribution studies in nude mice bearing a human colonic tumor xenograft were performed with these labeled conjugates, and comparisons were made to unconjugated NP-4 IgG and fragments labeled with 131I. Regardless of the labeling method, higher tumor uptake was found with the intact IgG than with the fragments, but due to faster blood clearance, tumor/blood ratios were higher for the fragments than for the IgG. Tumor uptake for the radiometal-labeled NP-4 was generally higher than the 131I-labeled NP-4. Tumor/nontumor ratios for the liver, kidney, and spleen were higher for the 111In- and 88Y-labeled NP-4 IgG than the respective radiometal-labeled fragments, but tumor/nontumor ratios for the 131I-NP-4 fragments were higher than the 131I-NP-4 IgG. Radiometal uptake in the kidney was approximately 8 and 150 times higher than the 131I-NP-4 F(ab')2 and Fab', respectively, and the clearance of radiometal activity in the kidneys was approximately 10 times slower than the radioiodine. Quantitation of 88Y or 111In activity in the femur showed 3-5%/g for the IgG and F(ab')2 and only 1-2%/g for the Fab'. The amount of radioactivity in the femur remained constant over time, and between 60 and 100% of the 88Y activity remained after flushing the core of the femur with saline, whereas 50-70% of the 111In and only 25-30% of the 131I activity remained after washing. Radiation dose estimates derived from these studies suggest that at the maximal tolerated dose 131I-NP-4 IgG would deliver 5.9 times the dose to the tumor as 90Y-labeled NP-4 IgG. 90Y-labeled fragments would not be useful due to higher doses to the kidneys than to the tumor. However, with 131I-labeled IgG and fragments there is greater flexibility to permit tumoricidal doses without excessive toxicity to the normal tissues.
Sharkey
R M
RM
Center for Molecular Medicine and Immunology, University of Medicine and Dentistry of New Jersey, Newark 07103.
Motta-Hennessy
C
C
Pawlyk
D
D
Siegel
J A
JA
Goldenberg
D M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000378:metabolism*; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011865:Radioisotope Dilution Technique; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes
D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D015021:Yttrium Radioisotopes