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Targeting Dendritic Cells with Antigen-Containing Liposomes

A Highly Effective Procedure for Induction of Antitumor Immunity and for Tumor Immunotherapy

¹ School of Biochemistry and Molecular Biology, Faculty of Science, ² Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia; ³ Institut Pasteur, Unitè de Gènètique Molèculaire Bactèrienne, Paris, France; and ⁴ The Centenary Institute of Cancer Medicine and Cell Biology and ⁵ Discipline of Medicine, University of Sydney, Sydney, New South Wales, Australia

Dendritic cells (DCs) are potent stimulators of immunity, and DCs pulsed with tumor antigen ex vivo have applications in tumor immunotherapy. However, DCs are a small population of cells, and their isolation and pulsing with antigen can be impractical. Here we show that a crude preparation of plasma membrane vesicles (PMV) from the highly metastatic murine melanoma (B16-OVA) and a surrogate tumor antigen (OVA) can be targeted directly to DCs in vivo to elicit functional effects. A novel metal-chelating lipid, 3(nitrilotriacetic acid)-ditetradecylamine, was incorporated into B16-OVA-derived PMV, allowing recombinant hexahistidine-tagged forms of single chain antibody fragments to the DC surface molecules CD11c and DEC-205, to be conveniently "engrafted" onto the vesicle surface by metal-chelating linkage. The modified PMV, or similarly engrafted synthetic stealth liposomes containing OVA or OVA peptide antigen, were found to target DCs in vitro and in vivo, in experiments using flow cytometry and fluorescence confocal microscopy. When used as vaccines in syngeneic mice, the preparations stimulated strong B16-OVA-specific CTL responses in splenic T cells and a marked protection against tumor growth. Protection was dependent on the simultaneous delivery of both antigen and a DC maturation or "danger signal" signal (IFN- or lipopolysaccharide). Administration of the DC-targeting vaccine to mice challenged with B16-OVA cells induced a dramatic immunotherapeutic effect and prolonged disease-free survival. The results show that the targeting of antigen to DCs in this way is highly effective at inducing immunity and protection against the tumor, with protection being at least partially dependent on the eosinophil chemokine eotaxin.

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