ArticleProceedings of the National Academy of Sciences of the United States of America2012
Identification and elimination of an immunodominant T-cell epitope in recombinant immunotoxins based on Pseudomonas exotoxin A.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 87 citations in OpenAlex.
- Review
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- Reducing Immunogenicity by Design: Approaches to Minimize Immunogenicity of Monoclonal Antibodies.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- Hosts and Heterologous Expression Strategies of Recombinant Toxins for Therapeutic Purposes.Toxins · 2023Review
- Bringing enzymes to the proximity party.RSC chemical biology · 2023Review
- A robust deep learning workflow to predict CD8 + T-cell epitopes.Genome medicine · 2023Article
- Cancer Drug Delivery Systems Using Bacterial Toxin Translocation Mechanisms.Bioengineering (Basel, Switzerland) · 2023Review
- Article
- Combining deep mutational scanning to heatmap of HLA class II binding of immunogenic sequences to preserve functionality and mitigate predicted immunogenicity.Frontiers in immunology · 2023Article
- Development of highly stable and de-immunized versions of recombinant alpha interferon: Promising candidates for the treatment of chronic and emerging viral diseases.Clinical immunology (Orlando, Fla.) · 2021Article
- Article
- Soluble Cytoplasmic Expression and Purification of Immunotoxin HER2(scFv)-PE24B as a Maltose Binding Protein Fusion.International journal of molecular sciences · 2021Article
- MHCEpitopeEnergy, a Flexible Rosetta-Based Biotherapeutic Deimmunization Platform.Journal of chemical information and modeling · 2021Article
- Globally deimmunized lysostaphin evades human immune surveillance and enables highly efficacious repeat dosing.Science advances · 2020Article
- Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors.Biomolecules · 2020Review
- Engineered Anti-GPC3 Immunotoxin, HN3-ABD-T20, Produces Regression in Mouse Liver Cancer Xenografts Through Prolonged Serum Retention.Hepatology (Baltimore, Md.) · 2020Article
- HER2-Specific Pseudomonas Exotoxin A PE25 Based Fusions: Influence of Targeting Domain on Target Binding, Toxicity, and In Vivo Biodistribution.Pharmaceutics · 2020Article
- Immunogenicity of Immunotoxins ContainingFrontiers in immunology · 2020Review
- GPI-AP: Unraveling a New Class of Malignancy Mediators and Potential Immunotherapy Targets.Frontiers in oncology · 2020Review
- Review
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 4 countries.
Funding
Abstract
Recombinant immunotoxins (RITs) are chimeric proteins that are being developed for cancer treatment. We have produced RITs that contain PE38, a portion of the bacterial protein Pseudomonas exotoxin A. Because the toxin is bacterial, it often induces neutralizing antibodies, which limit the number of treatment cycles and the effectiveness of the therapy. Because T cells are essential for antibody responses to proteins, we adopted an assay to map the CD4(+) T-cell epitopes in PE38. We incubated peripheral blood mononuclear cells with an immunotoxin to stimulate T-cell expansion, followed by exposure to overlapping peptide fragments of PE38 and an IL-2 ELISpot assay to measure responses. Our observation of T-cell responses in 50 of 50 individuals correlates with the frequency of antibody formation in patients with normal immune systems. We found a single, highly immunodominant epitope in 46% (23/50) of the donors. The immunodominant epitope is DRB1-restricted and was observed in subjects with different HLA alleles, indicating promiscuity. We identified two amino acids that, when deleted or mutated to alanine, eliminated the immunodominant epitope, and we used this information to construct mutant RITs that are highly cytotoxic and do not stimulate T-cell responses in many donors.
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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.