Overview of cell-based tools for pre-clinical assessment of immunogenicity of biotherapeutics.

With the increasing number of biotherapeutic drugs entering clinical trials, drug-induced immunogenicity becomes more and more a topic in immunotoxicology of drug development. Immunogenicity relies on the induction or presence of antibodies recognizing a biotherapeutic protein after its administration. Anti-drug antibodies (ADA) that may either bind to a protein drug and/ or neutralize its potency may modulate the pharmacokinetics of therapeutic proteins or evoke adverse events, ranging from hypersensitivity to autoimmune reactions. Screening for binding and neutralizing ADA is integral part of the monitoring program of biotherapeutics in clinical studies. In light of the availability of powerful in silico and in vitro tools for immunogenicity risk assessment, de-risking possibilities during pre-clinical development have become worth being considered. This review, which summarizes a presentation from the Conference on Immunogenicity for Biologics, gives an overview on novel cell-based approaches in immunogenicity risk assessment in the lead optimization phase of biotherapeutics. In particular, a strategy combining a human dendritic cell and a mass spectrometry analysis is compared with in silico algorithms as to its suitability to identify T-cell epitopes conferring immunogenicity. Moreover, the possibility of utilizing T-cell activation assays to rank lead candidates according to their immunogenicity potential is discussed. Finally, a strategy is outlined as to how the results of cell-based risk assessment tools can be exploited to reduce the immunogenicity of biotherapeutic proteins in the future.