TISSUE DISTRIBUTION AND RECEPTOR-MEDIATED CLEARANCE OF ANTI-CD11A ANTIBODY IN MICE (original) (raw)
Research ArticleArticle
, Judith A. Fox, Susanne Pippig, Susan Palmieri, Barbara Reitz, Michelle Gonzales, Anahid Bakshi, Josette Padilla-Eagar and Paul J. Fielder
Drug Metabolism and Disposition May 2005, 33 (5) 623-629; DOI: https://doi.org/10.1124/dmd.104.002584
Abstract
Efalizumab (Raptiva) is a humanized monoclonal antibody specific for CD11a, the α-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.
Footnotes
Financial support for this work was provided by Genentech, Inc.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.104.002584.
ABBREVIATIONS: LFA-1, lymphocyte function-associated antigen 1; ICAM-1, intercellular adhesion molecule 1; PBMC, peripheral blood mononuclear cell; WBA, whole body autoradiography; FACS, fluorescence-activated cell sorting; MFI, mean fluorescent intensity; PE, phosphatidylethanolamine; PerCP, peridinin chlorophyll-alpha protein; NK, natural killer; APC, allophycocyanin.
- Received October 4, 2004.
- Accepted January 21, 2005.
The American Society for Pharmacology and Experimental Therapeutics
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