An example using D-amino acids in relative binding position 1 (P1) of the PADRE peptide is presented. As demonstrated here, these in vitro binding studies are usually performed with known ligands which have been modified to contain UAA in HLA anchor positions. Next, this article discusses how HLA binding studies can be used to estimate the binding potentials of commonly encountered UAA and “correct” in silico estimates of binding based on their naturally occurring counterparts. Examples demonstrating in silico immunogenicity prediction for product impurities that are commonly found in formulations of the generic peptides teriparatide and semaglutide are provided. In silico assessment of immunogenic potential allows for risk-based selection of best candidate peptides in further confirmatory in vitro, ex vivo, and in vivo assays, thereby reducing the overall cost of immunogenicity evaluation. The authors developed an in silico method for modeling the impact of a given UAA on a peptide’s likelihood of binding to HLA and, by extension, its immunogenic potential. Both scenarios warrant the need for enhanced predictive tools. To date, the HLA binding properties of peptides containing UAA are not accurately estimated by most algorithms. In addition to commonly occurring in synthetic peptide impurities, unnatural amino acids (UAA) are also often incorporated into novel peptide therapeutics to improve properties of the drug product.
Immunoinformatics tools, such as the EpiMatrix algorithm, have been developed to screen natural amino acid sequences for peptides that will bind HLA. T cell epitopes bind human leukocyte antigen (HLA) by a well-characterized interaction of amino acid side chains and pockets in the HLA molecule binding groove. The in silico prediction of T cell epitopes within any peptide or biologic drug candidate serves as an important first step for assessing immunogenicity. EpiVax, Inc., Providence, RI, United States.
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