Direct Delivery of Antigens to Dendritic Cells via Antibodies Specific for Endocytic Receptors as a Promising Strategy for Future Therapies

Abstract

Dendritic cells (DCs) are the most potent professional antigen presenting cells and are therefore indispensable for the control of immunity. The technique of antibody mediated antigen targeting to DC subsets has been the basis of intense research for more than a decade. Many murine studies have utilized this approach of antigen delivery to various kinds of endocytic receptors of DCs both in vitro and in vivo. Today, it is widely accepted that different DC subsets are important for the induction of select immune responses. Nevertheless, many questions still remain to be answered, such as the actual influence of the targeted receptor on the initiation of the immune response to the delivered antigen. Further efforts to better understand the induction of antigen-specific immune responses will support the transfer of this knowledge into novel treatment strategies for human diseases. In this review, we will discuss the state-of-the-art aspects of the basic principles of antibody mediated antigen targeting approaches. A table will also provide a broad overview of the latest studies using antigen targeting including addressed DC subset, targeted receptors, outcome, and applied coupling techniques.

Keywords: CLR; DC; DCIR; DEC205; antigen targeting; antigen targeting antibodies; cancer; dendritic cell subsets; moDC; vaccine.

Figure 1

Principles of the use of human dendritic cells (DCs) for the treatment of diseases. There are two principal approaches to use DCs for the treatment of patients either by (a) using monocyte-derived DCs (moDCs) or by (b) directly targeting DCs in the patient using DC-targeting antibodies coupled to antigens. (a) For the vaccination of patients with their own moDCs, monocytes are isolated from the blood of the patient and differentiated into moDCs by culturing them in media containing GM-CSF and IL-4 for 5–6 days. Subsequently, cells are loaded with antigens and either matured with adjuvants (e.g., cytokine cocktail consisting of IL-1β, IL-6, TNFα, and PGE₂) or kept immature. These cells presenting peptides of the antigen as peptide-MHC complexes on their surface are then transfused back into the patient to induce either an inflammatory T cell response (matured DCs) or tolerance (immature DCs); (b) in an alternative approach, antigens are targeted directly to DCs in vivo by fusion of the antigen to antibodies directed against DC surface molecules. After binding to the DCs, the antibodies are internalized, processed, and presented on MHC class I and II molecules on the DC surface. Analogous to moDCs, the DCs induce an inflammatory T cell response in the presence of adjuvants such as toll like receptor (TLR) ligands or tolerance, if the antibody is injected alone without adjuvant. By usage of antibodies directed against surface molecules selectively expressed on one DC subset (here differentially colored in red, green, and blue), the type of immune response can be further regulated due to different functions of the DC subsets. Templates from Servier Medical Art (www.servier.com) were used and adapted for this figure.