Antibody targeted liposomes containing poly(rI).poly(rC) exert a specific antiviral and toxic effect on cells primed with interferons alpha/beta or gamma.
Double-stranded RNA can stimulate interferon production and mediate an antiproliferative effect on certain cell types. We evaluated the possibility of specifically targeting to cells in vitro the RNA duplex poly(rI).poly(rC) in pharmacologically active form after its encapsulation in small, unilamellar liposomes, to which was covalently coupled protein A. These liposomes became bound to and were endocytosed by murine L929 cells in the presence of protein A-binding monoclonal antibodies specific for an expressed cell surface protein, the H-2K molecule. When L929 cells were preincubated in the presence of low doses of interferon alpha/beta or gamma, they could be activated to produce interferon following exposure to either free poly(rI).poly(rC), or specifically bound liposomes poly(rI).poly(rC), but not the same liposomes in the presence of non-cell binding control antibodies. Specifically bound liposome-encapsulated poly(rI).poly(rC) was toxic to L929 cells at dose levels at least three logs lower than free poly(rI).poly(rC). This toxicity was also dependent on pre-treatment with interferon. These results indicate that liposome-encapsulated poly(rI).poly(rC) can survive endocytosis and can be released in active form to specific cell populations, at concentrations much lower than that required for pharmacologic effects of the same molecule in free form. They suggest that introduction into cells of other nucleic acids might benefit from the antibody-targeted liposome technology described here.
Milhaud
P G
PG
Laboratoire de Biochimie des Protéines, URA CNRS 1191, Université des Sciences et Techniques du Languedoc, Montpellier, France.
Machy
P
P
Lebleu
B
B
Leserman
L
L
D000818:Animals; D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis; D006183:H-2 Antigens / Q000276:immunology; D000922:Immunotoxins / Q000494:pharmacology*; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008081:Liposomes; D051379:Mice; D011070:Poly I-C / Q000008:administration & dosage* / Q000494:pharmacology; D013205:Staphylococcal Protein A / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D006183:H-2 Antigens; D000922:Immunotoxins; D007370:Interferon Type I; D008081:Liposomes; D013205:Staphylococcal Protein A; D007371:Interferon-gamma; D011070:Poly I-C