ArticleCellular and molecular life sciences : CMLS2014
Computationally driven deletion of broadly distributed T cell epitopes in a biotherapeutic candidate.
Article in Cellular and molecular life sciences : CMLS, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Machine-guided dual-objective protein engineering for deimmunization and therapeutic functions.Cell systems · 2025Article
- Strategies to Reduce the Immunogenicity of Recombinant Immunotoxins.The American journal of pathology · 2018Review
- QM/MM Description of Newly Selected Catalytic Bioscavengers Against Organophosphorus Compounds Revealed Reactivation Stimulus Mediated by Histidine Residue in the Acyl-Binding Loop.Frontiers in pharmacology · 2018Article
- Development of a strategy and computational application to select candidate protein analogues with reduced HLA binding and immunogenicity.Immunology · 2018Article
- Computationally optimized deimmunization libraries yield highly mutated enzymes with low immunogenicity and enhanced activity.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- EpiSweep: Computationally Driven Reengineering of Therapeutic Proteins to Reduce Immunogenicity While Maintaining Function.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Role of HLA-DP in the Presentation of Epitopes from the Truncated Bacterial PE38 Immunotoxin.The AAPS journal · 2017Article
- Design and engineering of deimmunized biotherapeutics.Current opinion in structural biology · 2016Review
- Poor correlation between T-cell activation assays and HLA-DR binding prediction algorithms in an immunogenic fragment of Pseudomonas exotoxin A.Journal of immunological methods · 2015Article
- Protein deimmunization via structure-based design enables efficient epitope deletion at high mutational loads.Biotechnology and bioengineering · 2015Article
- Structure-based design of combinatorial mutagenesis libraries.Protein science : a publication of the Protein Society · 2015Article
- Structure-based redesign of lysostaphin yields potent antistaphylococcal enzymes that evade immune cell surveillance.Molecular therapy. Methods & clinical development · 2015Article
- Mapping the Pareto optimal design space for a functionally deimmunized biotherapeutic candidate.PLoS computational biology · 2015Article
- Article
- Pareto Optimization of Combinatorial Mutagenesis Libraries.IEEE/ACM transactions on computational biology and bioinformaticsArticle
- Review
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6 authors.
Funding
Abstract
Biotherapeutics are subject to immune surveillance within the body, and anti-biotherapeutic immune responses can compromise drug efficacy and patient safety. Initial development of targeted antidrug immune memory is coordinated by T cell recognition of immunogenic subsequences, termed "T cell epitopes." Biotherapeutics may therefore be deimmunized by mutating key residues within cognate epitopes, but there exist complex trade-offs between immunogenicity, mutational load, and protein structure-function. Here, a protein deimmunization algorithm has been applied to P99 beta-lactamase, a component of antibody-directed enzyme prodrug therapies. The algorithm, integer programming for immunogenic proteins, seamlessly integrates computational prediction of T cell epitopes with both 1- and 2-body sequence potentials that assess protein tolerance to epitope-deleting mutations. Compared to previously deimmunized P99 variants, which bore only one or two mutations, the enzymes designed here contain 4-5 widely distributed substitutions. As a result, they exhibit broad reductions in major histocompatibility complex recognition. Despite their high mutational loads and markedly reduced immunoreactivity, all eight engineered variants possessed wild-type or better catalytic activity. Thus, the protein design algorithm is able to disrupt broadly distributed epitopes while maintaining protein function. As a result, this computational tool may prove useful in expanding the repertoire of next-generation biotherapeutics.
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