Received for publication October 12, 2004.
Revised January 19, 2005.
Accepted for publication January 21, 2005.

Tissue Distribution and Receptor-Mediated Clearance of anti-CD11a Antibody in Mice

Abstract

Efalizumab (Raptiva^TM) is a humanized monoclonal antibody specific for CD11a, the -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 following 72 h. At least a portion of the antibody was internalized and cleared by PBMC's, lymphocytes, and splenocytes in a time-dependent manner in vivo. Internalized antibody co-stained 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.

Key words: antibodies, distribution, drug clearance, drug disposition, drug distribution, immunotherapy, monoclonal antibody

This article has been cited by other articles:

				J. J. Lammerts van Bueren, W. K. Bleeker, H. O. Bogh, M. Houtkamp, J. Schuurman, J. G.J. van de Winkel, and P. W.H.I. Parren Effect of Target Dynamics on Pharmacokinetics of a Novel Therapeutic Antibody against the Epidermal Growth Factor Receptor: Implications for the Mechanisms of Action. Cancer Res., August 1, 2006; 66(15): 7630 - 7638. [Abstract] [Full Text] [PDF]

				S. Alcon-LePoder, M.-T. Drouet, P. Roux, M.-P. Frenkiel, M. Arborio, A.-M. Durand-Schneider, M. Maurice, I. Le Blanc, J. Gruenberg, and M. Flamand The Secreted Form of Dengue Virus Nonstructural Protein NS1 Is Endocytosed by Hepatocytes and Accumulates in Late Endosomes: Implications for Viral Infectivity J. Virol., September 1, 2005; 79(17): 11403 - 11411. [Abstract] [Full Text] [PDF]