Antibodies internalization mechanisms by dendritic cells and their role in therapeutic antibody immunogenicity

Internalization and processing by antigen-presenting cells such as dendritic cells (DCs) are critical steps for initiating a T-cell response to therapeutic antibodies. Consequences are the production of neutralizing antidrug antibodies altering the clinical response, the presence of immune complexes, and, in some rare cases, hypersensitivity reactions. In recent years, significant progress has been made in the knowledge of cellular uptake mechanisms of antibodies in DCs. The uptake of antibodies could be directly related to their immunogenicity by regulating the quantity of materials entering the DCs in relation to antibody structure. Here, we summarize the latest insights into cellular uptake mechanisms and pathways in DCs. We highlight the approaches to study endocytosis, the impact of endocytosis routes on T-cell response, and discuss the link between how DCs internalize therapeutic antibodies and the potential mechanisms that could give rise to immunogenicity. Understanding these processes could help in developing assays to evaluate the immunogenicity potential of biotherapeutics. Therapeutic antibodies internalization and processing by dendritic cells (DC) are critical steps in initiating T-cell-dependent antidrug-antibodies production. Here, we review the uptake mechanisms in DCs and how they influence the T-cell response and propose introducing DC antibody internalization as an immunogenicity risk assessment tool.image