ArticlePLoS computational biology2015
Mapping the Pareto optimal design space for a functionally deimmunized biotherapeutic candidate.
Article in PLoS computational biology, 2015. 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, 24 citations in OpenAlex.
- Beyond affinity: AI-supported developability assessment and multi-objective optimization in antibody development.Antibody therapeutics · 2026Review
- Resistor: An algorithm for predicting resistance mutations via Pareto optimization over multistate protein design and mutational signatures.Cell systems · 2022Article
- Co-optimization of therapeutic antibody affinity and specificity using machine learning models that generalize to novel mutational space.Nature communications · 2022Article
- Deep Neural Network-Assisted Drug Recommendation Systems for Identifying Potential Drug-Target Interactions.ACS omega · 2022Article
- TransDTI: Transformer-Based Language Models for Estimating DTIs and Building a Drug Recommendation Workflow.ACS omega · 2022Article
- DeepCPI: A Deep Learning-based Framework for Large-scale in silico Drug Screening.Genomics, proteomics & bioinformatics · 2019Article
- Balancing sensitivity and specificity in distinguishing TCR groups by CDR sequence similarity.BMC bioinformatics · 2019Article
- Searching for the Pareto frontier in multi-objective protein design.Biophysical reviews · 2017Review
- 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
- Design and engineering of deimmunized biotherapeutics.Current opinion in structural biology · 2016Review
- Large-scale Direct Targeting for Drug Repositioning and Discovery.Scientific reports · 2015Article
- Protein deimmunization via structure-based design enables efficient epitope deletion at high mutational loads.Biotechnology and bioengineering · 2015Article
- Article
- Structure-based redesign of lysostaphin yields potent antistaphylococcal enzymes that evade immune cell surveillance.Molecular therapy. Methods & clinical development · 2015Article
- Pareto Optimization of Combinatorial Mutagenesis Libraries.IEEE/ACM transactions on computational biology and bioinformaticsArticle
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The immunogenicity of biotherapeutics can bottleneck development pipelines and poses a barrier to widespread clinical application. As a result, there is a growing need for improved deimmunization technologies. We have recently described algorithms that simultaneously optimize proteins for both reduced T cell epitope content and high-level function. In silico analysis of this dual objective design space reveals that there is no single global optimum with respect to protein deimmunization. Instead, mutagenic epitope deletion yields a spectrum of designs that exhibit tradeoffs between immunogenic potential and molecular function. The leading edge of this design space is the Pareto frontier, i.e. the undominated variants for which no other single design exhibits better performance in both criteria. Here, the Pareto frontier of a therapeutic enzyme has been designed, constructed, and evaluated experimentally. Various measures of protein performance were found to map a functional sequence space that correlated well with computational predictions. These results represent the first systematic and rigorous assessment of the functional penalty that must be paid for pursuing progressively more deimmunized biotherapeutic candidates. Given this capacity to rapidly assess and design for tradeoffs between protein immunogenicity and functionality, these algorithms may prove useful in augmenting, accelerating, and de-risking experimental deimmunization efforts.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.