title: Structure-based redesign of proteins for minimal T-cell epitope content.
abstract: The protein universe displays a wealth of therapeutically relevant activities, but T-cell driven immune responses to non-"self" biological agents present a major impediment to harnessing the full diversity of these molecular functions. Mutagenic T-cell epitope deletion seeks to mitigate the immune response, but can typically address only a small number of epitopes. Here, we pursue a "bottom-up" approach that redesigns an entire protein to remain native-like but contain few if any immunogenic epitopes. We do so by extending the Rosetta flexible-backbone protein design software with an epitope scoring mechanism and appropriate constraints. The method is benchmarked with a diverse panel of proteins and applied to three targets of therapeutic interest. We show that the deimmunized designs indeed have minimal predicted epitope content and are native-like in terms of various quality measures, and moreover that they display levels of native sequence recovery comparable to those of non-deimmunized designs.
authors.affiliation: Department of Computer Science, Dartmouth College, New Hampshire 03755, USA.
authors.forename: Yoonjoo
authors.initials: Y
authors.lastname: Choi
authors.forename: Karl E
authors.initials: KE
authors.lastname: Griswold
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey-Kellogg
mesh_terms: D019295:Computational Biology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000276:immunology*; D012984:Software
chemical_list: D018984:Epitopes, T-Lymphocyte; D011506:Proteins