Tissue distribution and receptor-mediated clearance of anti-CD11a antibody in mice.
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.
Coffey
Greg P
GP
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., South San Francisco, CA 94080, USA.
Fox
Judith A
JA
Pippig
Susanne
S
Palmieri
Susan
S
Reitz
Barbara
B
Gonzales
Michelle
M
Bakshi
Anahid
A
Padilla-Eagar
Josette
J
Fielder
Paul J
PJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D001345:Autoradiography; D001853:Bone Marrow / Q000378:metabolism; D040881:CD11a Antigen / Q000276:immunology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009504:Neutrophils / Q000378:metabolism; D011946:Receptors, Antigen / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040881:CD11a Antigen; D011946:Receptors, Antigen; C472181:efalizumab