The effects of local hyperthermia on the catabolism of a radioiodinated chimeric monoclonal antibody.
Local hyperthermia has been shown to increase the tumor uptake and tumor:normal tissue ratios of radiolabeled monoclonal antibodies (mAbs) in athymic mouse xenograft models. The current study was undertaken to determine whether this behavior was related in part to alterations in mAb catabolism by local hyperthermia. Human/mouse chimeric 81C6 mAb reactive with tenascin and a nonspecific control mAb were labeled with 125I using Iodo-Gen and given to separate groups of athymic mice bearing s.c. D-54 MG human glioma xenografts. Half of the animals were then subjected to 4-h tumor-localized hyperthermia at 41.8 degrees C, a protocol previously shown to enhance the specific tumor uptake of the mAb in this xenograft model. The tumor, serum, liver, kidney, and urine were collected from heated as well as control animals 4 and 24 h after injection of the mAb and analyzed by SDS-PAGE and trichloroacetic acid precipitation. At 24 h, a significantly higher percentage of 81C6 was present as intact mAb in the tumors harvested from heated animals compared with those from controls. Unexpectedly, intact mAb was found in the urine of mice immediately after hyperthermia, but not in unheated control animals. We conclude that local hyperthermia decreases the catabolism of the mAb in the tumor and increases the urinary excretion of the mAb through a transient increase in glomerular permeability.
Hauck
M L
ML
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Zalutsky
M R
MR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000493:pharmacokinetics; D004591:Electrophoresis, Polyacrylamide Gel; D005910:Glioma / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced; D000922:Immunotoxins / Q000378:metabolism* / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000378:metabolism* / Q000493:pharmacokinetics; D012967:Sodium Dodecyl Sulfate; D019063:Tenascin / Q000276:immunology; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014238:Trichloroacetic Acid / Q000737:chemistry
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D011993:Recombinant Fusion Proteins; D019063:Tenascin; D012967:Sodium Dodecyl Sulfate; D014238:Trichloroacetic Acid