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- Title
Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti-CD40 antibody (SGN-40) in rodents and non-human primates.
- Authors
Kelley, Sean K.; Gelzleichter, Thomas; Dong Xie; Lee, Wyne P.; Darbonne, Walter C.; Qureshi, Ferhan; Kissler, Kim; Oflazoglu, Ezogelin; Grewal, Iqbal S.
- Abstract
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.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.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.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; published online 10 July 2006
- Subjects
B cells; ANIMAL models in research; PHARMACODYNAMICS; PHARMACOKINETICS; IMMUNOGLOBULINS; CANCER
- Publication
British Journal of Pharmacology, 2006, Vol 148, Issue 8, p1116
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0706828