Liposome-associated tumor necrosis factor retains bioactivity in the presence of neutralizing anti-tumor necrosis factor antibodies.
Cell-associated TNF-alpha, either bound to its receptor on monocyte membranes or expressed as an integral membrane protein, can exert potent tumor cytolytic activity. We assessed the interaction of TNF with the lipid bilayer membrane system, liposomes, and the effects of membrane association on TNF bioactivity. High levels of TNF can be encapsulated within liposomes. At neutral pH, TNF binds to the surface of preformed liposomes (liposome-associated TNF), but does not partition into the lipid bilayer. TNF appears to bind to negatively charged phospholipid head groups of the outer membrane leaflet. Free TNF, liposome-associated TNF, and liposome-encapsulated TNF display comparable abilities to activate human peripheral blood monocytes and to lyse tumor cells. However, liposome-encapsulated TNF, as well as TNF bound to the outer surface of preformed liposomes, retains bioactivity in the presence of anti-TNF antibodies that neutralize free TNF. The interaction of liposomal TNF with cell surface TNF receptors thus appears to be preserved in the presence of neutralizing antibodies.
Debs
R J
RJ
Cancer Research Institute, University of California, San Francisco 94143-0128.
Düzgüneş
N
N
Brunette
E N
EN
Fendly
B
B
Patton
J
J
Philip
R
R
D000328:Adult; D000906:Antibodies / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008051:Lipid Bilayers / Q000276:immunology; D008081:Liposomes / Q000276:immunology* / Q000494:pharmacology; D008262:Macrophage Activation; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009500:Neutralization Tests; D010539:Permeability; D011994:Recombinant Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D007375:Interleukin-1; D008051:Lipid Bilayers; D008081:Liposomes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone