Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics.

One of the great surprises of the biologics revolution has been the discovery that recombinant human proteins, including monoclonals of human origin, can cause immune responses when administered to immune-competent subjects. Preclinical and clinical evaluations of the potential immunogenicity of biologics have been primarily focused on humoral immune responses and as a result, the critical contribution of T cells to the development of anti-monoclonal antibodies (also known as anti-drug antibodies or ADA) has been somewhat overlooked. Recent publications have confirmed the role of effector T cells and begun to explore the role of regulatory T cells in the development of anti-drug antibodies. This review will focus on the role of T-cell-dependent (Td) immunogenicity assessment in the preclinical and clinical phases of drug development and summarize new data on regulatory T-cell epitopes contained in the Fc and CH1 domains of IgG. Recommendations for Td immunogenicity screening and assessment provided in this article may contribute to the development of safer protein-based drugs for human use.