Antibody-dependent difference in biodistribution of monoclonal antibodies in animal models and humans.
The study was designed to clarify the difference in pharmacokinetics of monoclonal antibodies (mAb) in animal models and humans, and to elucidate the applicability of animal models. 99mTc-labeled murine mAb -- against carcinoembryonic antigen (designated BW431/26), and neural cell adhesion molecule (NE150) -- and one chimeric mouse/human mAb against nonspecific cross-reacting antigen (chNCA) were administered i.v. to normal mice and athymic mice (370 kBq, 400 ng) xenografted with human cancer cells expressing antigens, and into patients with tumor (925 MBq, 1 mg). The biodistribution of two of the three mAb (not 99mTc-BW431/26) differed clearly in mice and patients. 99mTc-NE150 showed specific uptake in xenografted tumor and otherwise a normal biodistribution; however, clinical examination showed increased uptake in the liver with rapid blood clearance (mean alpha half-life = 31.1 min) compared with 99mTc-BW431/26 (28.4 h). 99mTc-chNCA demonstrated increased blood clearance and renal excretion in both normal and athymic mice, with accumulation in tumors. Clinical examination showed rapid blood clearance (mean alpha half-life = 6.4 min) and increased uptake in the liver. High-performance liquid chromatographic analysis of 99mTc-chNCA revealed the immune complex in blood, suggesting uptake of the complex by the reticuloendothelial cells. The biodistribution of radiolabeled mAb in animal and human models was variable and specific for each of the three mAb. The results of animal studies with mAb should be evaluated carefully before being extrapolated to humans, on the basis of the nature of the mAb and interacting substances.
Oriuchi
N
N
Department of Nuclear Medicine, Gunma University School of Medicine, Maebashi, Japan.
Watanabe
N
N
Kanda
H
H
Hashimoto
M
M
Sugiyama
S
S
Takenoshita
S
S
Imai
K
K
Ueda
R
R
Endo
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000936:Antigen-Antibody Complex / Q000097:blood; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015815:Cell Adhesion Molecules; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008175:Lung Neoplasms; D008562:Membrane Glycoproteins / Q000276:immunology; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D012157:Mononuclear Phagocyte System / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D009368:Neoplasm Transplantation; D019006:Neural Cell Adhesion Molecules / Q000276:immunology; D009928:Organ Specificity; D055503:Protein Multimerization; D013045:Species Specificity; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules