Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti‐CD40 antibody (SGN‐40) in rodents and non‐human primates

1 Cell‐surface expression of CD40 in B‐cell malignancies and multiple solid tumors has raised interest in its potential use as a target for antibody‐based cancer therapy. SGN‐40, a humanized monoclonal anti‐CD40 antibody, mediates antibody‐dependent cytotoxicity and inhibits B‐cell tumor growth in vitro, properties of interest for the treatment of cancers, and is currently in Phase I clinical trials for B‐cell malignancies. In this study, we determined in vivo activity and pharmacokinetics properties of SGN‐40. 2 Effect of SGN‐40 in xenograft model of CD40‐expressing B‐cell lymphoma in severe‐combined immune deficiency mice and its in vivo pharmacokinetics properties in normal mice, rats and cynomolgus monkeys were studied. 3 Treatment with SGN‐40 significantly increased the survival of mice xenografted with human B‐cell lymphoma cell line. SGN‐40 exhibited nearly 100% bioavailability in mice and it cleared faster when given at a low dose. In monkeys, clearance of SGN‐40 was also much faster at low dose, suggesting nonlinear pharmacokinetics in these species. In rats, however, SGN‐40 clearance at all tested doses was similar, suggesting that pharmacokinetics were linear in this dose range in rats. Administration of SGN‐40 to monkeys also produced marked, dose‐dependent, and persistent depletion of peripheral CD20+ B lymphocytes. 4 Data presented in this report suggest that SGN‐40 is active in in vivo, and based upon interspecies scaling, SGN‐40 clearance in humans is predicted to be similar to observed SGN‐40 clearance in monkeys. These data suggest that SGN‐40 has appropriate pharmacokinetic properties that support its clinical use. British Journal of Pharmacology (2006) 148, 1116–1123. doi:10.1038/sj.bjp.0706828