In vitro internalization, intracellular transport, and clearance of an anti-CD11a antibody (Raptiva) by human T-cells.
Efalizumab (Raptiva) is a humanized CD11a-specific monoclonal antibody that was recently approved for the treatment of moderate to severe psoriasis. In psoriasis patients, the rate of efalizumab clearance from serum is related to T-cell surface expression of CD11a, suggesting a receptor-mediated clearance model for efalizumab (Bauer et al., 1999). However, limited experimental data are available to explain how the interaction with CD11a results in the systemic clearance of efalizumab. The following studies were designed to test the hypothesis that one mechanism of anti-CD11a antibody clearance is mediated in part by cellular internalization. This was tested in vitro using purified mouse and human T-cells as a model to study the cellular uptake and clearance of anti-CD11a antibodies. Data from these studies suggest that anti-CD11a antibodies are internalized by purified T-cells. Upon internalization, the antibodies appeared to be targeted to lysosomes and were cleared from within the cells in a time-dependent manner. CD11a-mediated internalization and lysosomal targeting of efalizumab may constitute one pathway by which this antibody is cleared in vivo.
Coffey
G P
GP
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., 1 DNA Way, Building 20, Room 201, South San Francisco, CA 94080, USA. gregcoffey1@yahoo.com
Stefanich
E
E
Palmieri
S
S
Eckert
R
R
Padilla-Eagar
J
J
Fielder
P J
PJ
Pippig
S
S
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D061067:Antibodies, Monoclonal, Humanized; D001692:Biological Transport; D040881:CD11a Antigen / Q000276:immunology*; D004347:Drug Interactions; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D013347:Subcellular Fractions / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040881:CD11a Antigen; D018942:Macrolides; C036978:concanamycin A; C472181:efalizumab