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Drug Metabolism and Disposition Fast Forward
First published on January 26, 2005; DOI: 10.1124/dmd.104.002584

0090-9556/05/3305-623-629$20.00
DMD 33:623-629, 2005

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TISSUE DISTRIBUTION AND RECEPTOR-MEDIATED CLEARANCE OF ANTI-CD11A ANTIBODY IN MICE

Greg P. Coffey, Judith A. Fox, Susanne Pippig, Susan Palmieri, Barbara Reitz, Michelle Gonzales, Anahid Bakshi, Josette Padilla-Eagar, and Paul J. Fielder

Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc. South San Francisco, California (G.P.C., S.Pi., S.Pa., M.G., A.B., J.P.-E., P.J.F.); and Department of Preclinical Pharmacology, Genencor International, Inc., Palo Alto, California (J.A.F., B.R.)

Efalizumab (Raptiva) is a humanized monoclonal antibody specific for CD11a, the {alpha}-chain component of the lymphocyte function-associated antigen 1. In humans, the rate of efalizumab elimination from serum was related to the level of CD11a cell surface expression. These data suggested a role for the CD11a receptor, itself, in efalizumab clearance. Recently, we conducted a series of in vitro studies that suggested a role for CD11a-expressing T cells in efalizumab clearance as mediated by cellular internalization and lysosome-mediated degradation (Coffey et al., 2004). To further study the mechanism of anti-CD11a clearance in vivo, we assessed the tissue distribution, cellular internalization, and subcellular localization of a rat anti-mouse CD11a monoclonal antibody in various tissues in mice. Anti-CD11a antibody primarily distributed to leukocytes and macrophages in the peripheral blood, spleen, and liver, with uptake in the lymph nodes and bone marrow after 72 h. At least a portion of the antibody was internalized and cleared by peripheral blood mononuclear cells, lymphocytes, and splenocytes in a time-dependent manner in vivo. Internalized antibody costained with LysoTracker Red, suggesting that it was transported to lysosomes for degradation. Together, these data suggest that one clearance mechanism for anti-CD11a antibody in vivo is via receptor-mediated internalization and lysosomal degradation by CD11a-expressing cells and tissues.

Address correspondence to: Dr. Paul J. Fielder, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. E-mail: pjf{at}gene.com




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