Trial reportThe Journal of biological chemistry2014
Mutations in subunit interface and B-cell epitopes improve antileukemic activities of Escherichia coli asparaginase-II: evaluation of immunogenicity in mice.
Trial report in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 39 citations in OpenAlex.
- Engineered L-asparaginase variants with enhanced therapeutic properties to improve treatment of childhood acute lymphatic leukemia.Cancer gene therapy · 2025Article
- Toward Safer Biotherapeutics: Expression and Characterization of a Humanized Chimeric L-Asparaginase inInternational journal of molecular sciences · 2025Article
- Investigating Functional and Folding Stability of an EngineeredAdvanced pharmaceutical bulletin · 2024Article
- Molecular Modeling and Optimization of Type II E.coli l-Asparginase Activity by in silico Design and in vitro Site-directed Mutagenesis.The protein journal · 2023Article
- Expression and Biological Evaluation of an Engineered Recombinant L-asparaginase Designed byAdvanced pharmaceutical bulletin · 2023Article
- Enzyme Engineering Strategies for the Bioenhancement of L-Asparaginase Used as a Biopharmaceutical.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2023Review
- In Silico Design of a Chimeric Humanized L-asparaginase.International journal of molecular sciences · 2023Article
- Insights into the Distribution and Functional Properties of l-Asparaginase in the Archaeal Domain and Characterization ofACS omega · 2022Article
- Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents.Molecules (Basel, Switzerland) · 2022Review
- Molecular Analysis of L-Asparaginases for Clarification of the Mechanism of Action and Optimization of Pharmacological Functions.Pharmaceutics · 2022Review
- Protein re-surfacing ofFrontiers in immunology · 2022Article
- Class II Human Leukocyte Antigen Variants Associate With Risk of Pegaspargase Hypersensitivity.Clinical pharmacology and therapeutics · 2021Article
- Deimmunization of protein therapeutics - Recent advances in experimental and computational epitope prediction and deletion.Computational and structural biotechnology journal · 2021Review
- Functional and structural evaluation of the antileukaemic enzyme L-asparaginase II expressed at low temperature by different Escherichia coli strains.Biotechnology letters · 2020Article
- Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts.Clinical cancer research : an official journal of the American Association for Cancer Research · 2020Article
- Article
- Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles.Frontiers in bioengineering and biotechnology · 2018Review
- Development ofACS omega · 2017Article
- Design and engineering of deimmunized biotherapeutics.Current opinion in structural biology · 2016Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
L-Asparaginase-II from Escherichia coli (EcA) is a central component in the treatment of acute lymphoblastic leukemia (ALL). However, the therapeutic efficacy of EcA is limited due to immunogenicity and a short half-life in the patient. Here, we performed rational mutagenesis to obtain EcA variants with a potential to improve ALL treatment. Several variants, especially W66Y and Y176F, killed the ALL cells more efficiently than did wild-type EcA (WT-EcA), although nonleukemic peripheral blood monocytes were not affected. Several assays, including Western blotting, annexin-V/propidium iodide binding, comet, and micronuclei assays, showed that the reduction in viability of leukemic cells is due to the increase in caspase-3, cytochrome c release, poly(ADP-ribose) polymerase activation, down-regulation of anti-apoptotic protein Bcl-XL, an arrest of the cell cycle at the G0/G1 phase, and eventually apoptosis. Both W66Y and Y176F induced significantly more apoptosis in lymphocytes derived from ALL patients. In addition, Y176F and Y176S exhibited greatly decreased glutaminase activity, whereas K288S/Y176F, a variant mutated in one of the immunodominant epitopes, showed reduced antigenicity. Further in vivo immunogenicity studies in mice showed that K288S/Y176F was 10-fold less immunogenic as compared with WT-EcA. Moreover, sera obtained from WT-EcA immunized mice and ALL patients who were given asparaginase therapy for several weeks recognized the K288S/Y176F mutant significantly less than the WT-EcA. Further mechanistic studies revealed that W66Y, Y176F, and K288S/Y176F rapidly depleted asparagine and also down-regulated the transcription of asparagine synthetase as compared with WT-EcA. These highly desirable attributes of these variants could significantly advance asparaginase therapy of leukemia in the future.
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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.