Major Histocompatibility Complex Binding, Eluted Ligands, and Immunogenicity: Benchmark Testing and Predictions

Antidrug antibody (ADA) responses impact drug safety, potency, and efficacy. It is generally assumed that ADA responses are associated with human leukocyte antigen (HLA) class II-restricted CD4+ T-cell reactivity. Although this review does not address ADA responses per se, the analysis presented here is relevant to the topic, because measuring or predicting CD4+ T-cell reactivity is a common strategy to address ADA and immunogenicity concerns. Because human CD4+ T-cell reactivity relies on the recognition of peptides bound to HLA class II, prediction, or measurement of the capacity of different peptides to bind or be natural ligands of HLA class II is used as a predictor of CD4+ T-cell reactivity and ADA development. Thus, three different interconnected variables are commonly utilized in predicting T-cell reactivity: major histocompatibility complex (MHC) binding, capacity to be generated as natural HLA ligands, and T-cell immunogenicity. To provide the scientific community with guidance in the relative merit of different approaches, it is necessary to clearly define what outcomes are being considered. Thus, the accuracy of HLA binding predictions varies as a function of what the outcome predicted is, whether it is binding itself, natural processing, or T-cell immunogenicity. Furthermore, it is necessary that the accuracy of prediction is based on rigorous benchmarking, grounded by fair, objective, transparent, and experimental criteria. In this review, we provide our perspective on how different variables and methodologies predict each of the various outcomes and point out knowledge gaps and areas to be addressed by further experimental work.