Other - Immunogenicity Screening
Cost-effective peptide synthesis methods are contributing to an influx of generic peptide drugs in the pharmaceuticals. Despite the rapidity and simplicity of peptide synthesis, regulatory agencies have raised concern about the potential for impurities introduced during the synthetic process that induce unwanted immune responses. These impurities are derived from the parent drug but may contain amino acid insertions, deletions, truncations and the incorporation of D-stereoisomers and non-natural amino acids. Any of these impurities can create new T cell epitopes within the peptide sequence resulting in unexpected immune responses.
Taspoglutide, used for the treatment on type 2 diabetes, failed during Phase III Clinical Trials due to the development of a hypersensitivity reaction in 38% of patients. Analysis of a typical batch used in the Phase III Trials revealed several manufacturing impurities. When it was determined that drug hypersensitivity was linked to HLA (DRB7 and DRB11), the developer suspected that the allergic reactions might be attributable to new T cell epitopes present only in the impurities. EpiMatrix analysis of impurities resulting from amino acid duplications reveals the creation of several neoepitopes when compared to the baseline sequence, five of which created neoepitopes predicted to bind HLA DR7 and DR11 supertype families that could have contributed to the observed hypersensitivity in subjects with DRB1*0701 and DRB1*1104.
In summary, this Taspoglutide case study illustrates the importance of identifying manufacturing related impurities and assessing their immunogenic potential. Methods for immunogenicity screening using silico and in vitro analysis will be described in this presentation.