Immunogenicity of protein aggregates--concerns and realities.

Protein aggregation is one of the key challenges in the development of protein biotherapeutics. It is a critical product quality issue as well as a potential safety concern due to the increased immunogenicity potential of these aggregates. The overwhelming safety concern has led to an increased development effort and regulatory scrutiny in recent years. The main purposes of this review are to examine the literature data on the relationship between protein aggregates and immunogenicity, to highlight the linkage and existing inconsistencies/uncertainties, and to propose directions for future investigations/development.