Tissue distribution and complex formation with IgE of an anti-IgE antibody after intravenous administration in cynomolgus monkeys.
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.
Fox
J A
JA
Department of Pharmacokinetics and Metabolism, Genentech, Inc. South San Francisco, California, USA.
Hotaling
T E
TE
Struble
C
C
Ruppel
J
J
Bates
D J
DJ
Schoenhoff
M B
MB
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism*; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D011994:Recombinant Proteins / Q000378:metabolism; D014018:Tissue Distribution
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; C026408:anti-IgE antibodies; D007073:Immunoglobulin E