ANTIBODY-DEPENDENT DIFFERENCE IN BIODISTRIBUTION OF MONOCLONAL-ANTIBODIES IN ANIMAL-MODELS AND HUMANS

The study was designed to clarify the difference in pharmacokinetics o f monoclonal antibodies (mAb) in animal models and humans, and to eluc idate the applicability of animal models. Tc-99m-labeled murine mAb ag ainst carcinoembryonic antigen (designated BW431/26), and neural cell adhesion molecule (NE150) - and one chimeric mouse/human mAb against n onspecific crossreacting antigen (chNCA) were administered i.v. to nor mal mice and athymic mice (370 kBq, 400 ng) xenografted with human can cer cells expressing antigens, and into patients with tumor (925 MBq, 1 mg). The biodistribution of two of the three mAb (not Tc-99m-BW431/2 6) differed clearly in mice and patients, Tc-99m-NE150 showed specific uptake in xenografted tumor and otherwise a normal biodistribution; h owever, clinical examination showed increased uptake in the liver with rapid blood clearance (mean alpha half-life = 31.1 min) compared with Tc-99m-BW431/26 (28.4 h). Tc-99m-chNCA demonstrated increased blood c learance and renal excretion in both normal and athymic mice, with acc umulation in tumors. Clinical examination showed rapid blood clearance (mean alpha half-life = 6.4 min) and increased uptake in the liver. H igh-performance liquid chromatographic analysis of Tc-99m-chNCA reveal ed the immune complex in blood, suggesting uptake of the complex by th e reticuloendothelial cells. The biodistribution of radiolabeled mAb i n animal and human models was variable and specific for each of the th ree mAb. The results of animal studies with mAb should be evaluated ca refully before being extrapolated to humans, on the basis of the natur e of the mAb and interacting substances.