Immunotoxicity and immunogenicity of biopharmaceuticals: design concepts and safety assessment

The biopharmaceutical market has grown steadily since the early 1980s and today over 150 protein biopharmaceuticals have been approved for clinical use. These products often exhibit forms of immunotoxicity that often only come to light during clinical studies. The predictive value of animal studies and traditional in vitro screens is questionable, with few existing methods able to predict immunotoxicity in a way that is useful for estimating risk for entire patient populations for a specific, and often unique, product. Here, the relative merits of rational design and alternative strategies for immunotoxicity testing are considered with reference to the outcomes of preclinical and clinical studies on biopharmaceuticals. Specific reference is made to the prediction of immunogenicity using organotypic models, transgenic models of autoimmunity and immunogenicity as well as rodent models of hypersensitivity, immunosuppression and immunostimulation. The role played by human cell-based assays and in silico prediction models that have been developed and validated for the assessment of chemical classes is also appraised.