Tissue distribution and complex formation with IgE of an anti-IgE antibody after intravenous administration in cynomolgus monkeys

JA Fox, TE Hotaling, C Struble, J Ruppel, DJ Bates and MB Schoenhoff

Department of Pharmacokinetics and Metabolism, Genentech, Inc. South San Francisco, California, USA.

A humanized antihuman IgE antibody, rhuMAb-E25, was designed to form complexes with free IgE, blocking its interaction with mast cells and basophils and thereby preventing the initiation of the allergic cascade. To characterize the rhuMAb-E25: IgE complexes formed in vivo and to examine the disposition of the antibody in a relevant animal model, 125I-rhuMAb-E25 was administered as an intravenous bolus dose to cynomolgus monkeys that have high levels of IgE. The pharmacokinetic values of unlabeled and radiolabeled antibody were similar, which indicated that the disposition of 125I-rhuMAb-E25 reflected that of rhuMAb-E25. Size-exclusion chromatography of serum samples showed that the rhuMAb-E25:IgE complexes were of limited size and were similar to the small complexes formed in vitro with human IgE. Pharmacokinetic analysis revealed that both rhuMAb-E25 and rhuMAb-E25:IgE complexes cleared the serum compartment, albeit slowly. No specific uptake of radioactivity was seen in any of the tissues collected from the cynomolgus monkeys at 1 hr and 96 hr postadministration; no association was observed between 125I-rhuMAb-E25, or the complexes, and blood cells. Urinary excretion was the primary route of elimination of radioactivity; > 90% of the radioactivity found in urine was not associated with protein. The lack of specific tissue uptake and blood cell association and the slow clearance of rhuMAb-E25:IgE complexes were consistent with low-avidity interaction of small complexes with Fc gamma receptors of leukocytes and the reticuloendothelial system.

Volume 279, Issue 2, pp. 1000-1008, 11/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				G. Pelaia, T. Renda, P. Romeo, M. T. Busceti, and R. Maselli Review: Omalizumab in the treatment of severe asthma: efficacy and current problems Therapeutic Advances in Respiratory Disease, December 1, 2008; 2(6): 409 - 421. [Abstract] [PDF]

				W. W. Busse, E. Israel, H. S. Nelson, J. W. Baker, B. L. Charous, D. Y. Young, V. Vexler, R. S. Shames, and the Daclizumab Asthma Study Group Daclizumab Improves Asthma Control in Patients with Moderate to Severe Persistent Asthma: A Randomized, Controlled Trial Am. J. Respir. Crit. Care Med., November 15, 2008; 178(10): 1002 - 1008. [Abstract] [Full Text] [PDF]

				G. Hanf, O. Noga, A. O'Connor, and G. Kunkel Omalizumab inhibits allergen challenge-induced nasal response Eur. Respir. J., March 1, 2004; 23(3): 414 - 419. [Abstract] [Full Text] [PDF]

				E. S. SCHULMAN Development of a Monoclonal Anti-Immunoglobulin E Antibody (Omalizumab) for the Treatment of Allergic Respiratory Disorders Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): S6 - 11. [Abstract] [Full Text] [PDF]

				H. Milgrom, W. Berger, A. Nayak, N. Gupta, S. Pollard, M. McAlary, A. F. Taylor, and P. Rohane Treatment of Childhood Asthma With Anti-Immunoglobulin E Antibody (Omalizumab) Pediatrics, August 1, 2001; 108 (2): e36 - e36. [Abstract] [Full Text] [PDF]

				H. Milgrom, R. B. Fick, J. Q. Su, J. D. Reimann, R. K. Bush, M. L. Watrous, W. J. Metzger, and The rhuMAb-E25 Study Group Treatment of Allergic Asthma with Monoclonal Anti-IgE Antibody N. Engl. J. Med., December 23, 1999; 341(26): 1966 - 1973. [Abstract] [Full Text] [PDF]

				C. Renard, O. Chappey, M. P. Wautier, M. Nagashima, J. Morser, J. M. Scherrmann, and J. L. Wautier The Human and Rat Recombinant Receptors for Advanced Glycation End Products Have a High Degree of Homology but Different Pharmacokinetic Properties in Rats J. Pharmacol. Exp. Ther., September 1, 1999; 290(3): 1458 - 1466. [Abstract] [Full Text]

				Y. S. Lin, C. Nguyen, J.-L. Mendoza, E. Escandon, D. Fei, Y. G. Meng, and N. B. Modi Preclinical Pharmacokinetics, Interspecies Scaling, and Tissue Distribution of a Humanized Monoclonal Antibody against Vascular Endothelial Growth Factor J. Pharmacol. Exp. Ther., January 1, 1999; 288(1): 371 - 378. [Abstract] [Full Text]