Pharmacokinetics of reshaped MAb 425 in three animal species

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Abstract
The murine monoclonal antibody (MAb) 425 (mMAb 425) directed against the human EGFR (epidermal growth factor receptor) was reshaped (rMAb 425) in order to improve its therapeutical potential in humans. The pharmacokinetic properties of [125I]-mMAb and [125I]-rMAb 425 were compared in three animal species. Whereas the clearance curves of both antibodies decreased biphasically in rats and nude mice bearing human mammary carcinoma, a monophasic decline was observed in Cynomolgus monkeys. Plasma elimination half-lives of murine and reshaped MAb 425 were similar, short in the monkey (26 h for mMAb 425 and 31 h for rMAb 425) and long in rats (240 h for mMAb 425 and 225 h for rMAb 425). In xenografted nude mice however, the half-life of mMAb 425 (203 h) was about twice as long as that of rMAb 425 (124 h). The half-lives of intact rMAb 425 in the three species obtained by ELISA differed at most by a factor of two from those obtained by radioactivity measurements. Biodistribution studies of [125I]-rMAb 425 revealed a tumor/blood ratio of 1.2 on d 1 and 5.1 on d 18, respectively. Fifty-four and thirty-eight percent of the radioactive dose were excreted with urine in nude mice (within 12 d) and rats (within 11 d), respectively. Specific localization of [125I]-rMAb 425 in human mammary carcinoma xenografted to nude mice was demonstrated.