In silico high throughput pre-clinical determination of monoclonal antibody immunogenicity (P3391)

Abstract

Abstract One of the great surprises of the biologics revolution has been the discovery that recombinant human proteins, including humanized and fully-human monoclonal antibodies (MAb), can be immunogenic when administered to immune-competent subjects. Preclinical and clinical evaluations of the immunogenic potential for biologic drugs primarily focus on humoral immune responses; as a result, the critical contribution of T cells to the development of anti-drug antibodies (ADA) has been somewhat overlooked. Using the EpiMatrix T cell epitope mapping system, we have developed an interactive in silico screening and optimization platform that evaluates the overall immunogenic potential of a biologic as well as identifies individual T cell epitope clusters contributing to its immunogenicity. In contrast to other immunogenicity prediction tools, our platform considers the contribution of regulatory T cell epitopes (Tregitopes) to immunogenic potential. Tregitopes are highly conserved T cell epitopes derived from IgG that we and others have shown activate regulatory T cells and promote tolerance induction to associated antigens. Here we demonstrate the correlation of available clinical immunogenicity data with Tregitope-adjusted immunogenicity scoring for twenty approved MAbs. Further, we present a high-throughput platform from which these scores can be used to triage large pools of candidate MAbs during the discovery phase of antibody development.