1. Medicine

Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical

  1. Elisabeth Gludovacz
  2. Kornelia Schuetzenberger
  3. Marlene Resch
  4. Katharina Tillmann
  5. Karin Petroczi
  6. Markus Schosserer
  7. Sigrid Vondra
  8. Serhii Vakal
  9. Gerald Klanert
  10. Jürgen Pollheimer
  11. Tiina A Salminen
  12. Bernd Jilma
  13. Nicole Borth
  14. Thomas Boehm  Is a corresponding author
  1. Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria
  2. Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Austria
  3. Department of Clinical Pharmacology, Medical University of Vienna, Austria
  4. Center for Biomedical Research, Medical University of Vienna, Austria
  5. University of Natural Resources and Life Sciences, Vienna, Austria
  6. Department of Obstetrics and Gynecology, Medical University of Vienna, Austria
  7. Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Finland
  8. Medical University of Vienna, Austria
  9. Department of Biotechnology, University of Natural Resources and Life Sciences, Austria
https://doi.org/10.7554/eLife.68542
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  1. Elisabeth Gludovacz
  2. Kornelia Schuetzenberger
  3. Marlene Resch
  4. Katharina Tillmann
  5. Karin Petroczi
  6. Markus Schosserer
  7. Sigrid Vondra
  8. Serhii Vakal
  9. Gerald Klanert
  10. Jürgen Pollheimer
  11. Tiina A Salminen
  12. Bernd Jilma
  13. Nicole Borth
  14. Thomas Boehm
(2021)
Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
eLife 10:e68542.
https://doi.org/10.7554/eLife.68542
  2. Download BibTeX
  3. Download .RIS

Abstract

Background: Excessive plasma histamine concentrations cause symptoms in mast cell activation syndrome, mastocytosis or anaphylaxis. Anti-histamines are often insufficiently efficacious. Human diamine oxidase (hDAO) can rapidly degrade histamine and therefore represents a promising new treatment strategy for conditions with pathological histamine concentrations.

Results: Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After replacement of positively charged amino acids of the heparin-binding motif with polar serine or threonine residues binding to heparin and heparan sulfate was strongly reduced. The double mutant rhDAO-R568S/R571T showed minimal cellular uptake. The short α-distribution half-life of the wildtype protein was eliminated and the clearance was significantly reduced in rodents.

Conclusions: The successful decrease in plasma clearance of rhDAO by mutations of the heparin-binding motif with unchanged histamine-degrading activity represents the first step towards the development of rhDAO as a first-in-class biopharmaceutical to effectively treat diseases characterized by excessive histamine concentrations in plasma and tissues.

Funding: Austrian Science Fund (FWF) Hertha Firnberg program grant T1135 (EG); ADD funding Sigrid Juselius Foundation, Medicinska Understödsförening Liv och Hälsa rft (TAS and SeV).

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2 and 3.

Article and author information

Author details

  1. Elisabeth Gludovacz

    Department of Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Vienna, Austria
    Competing interests
    Elisabeth Gludovacz, is named as an inventor with The Medical University of Vienna and the University of Natural Resources and Life Sciences of a patent describing the rhDAO heparin-binding motif mutants presented herein (patent pending WO2020169577A1).

  2. Kornelia Schuetzenberger

    Center for Medical Physics and Biomedical Engineering, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.

  3. Marlene Resch

    Department of Clinical Pharmacology, Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.

  4. Katharina Tillmann

    Center for Biomedical Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.

  5. Karin Petroczi

    Department of Clinical Pharmacology, Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.

  6. Markus Schosserer

    Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2025-0739

  7. Sigrid Vondra

    Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.

  8. Serhii Vakal

    Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
    Competing interests
    No competing interests declared.

  9. Gerald Klanert

    Department of Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.

  10. Jürgen Pollheimer

    Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8440-5221

  11. Tiina A Salminen

    Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
    Competing interests
    No competing interests declared.

  12. Bernd Jilma

    Department of Clinical Pharmacology, Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
    Competing interests
    Bernd Jilma, is named as an inventor with The Medical University of Vienna and the University of Natural Resources and Life Sciences of a patent describing the rhDAO heparin-binding motif mutants presented herein (patent pending WO2020169577A1)..

  13. Nicole Borth

    Department of Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria
    Competing interests
    Nicole Borth, is named as an inventor with The Medical University of Vienna and the University of Natural Resources and Life Sciences of a patent describing the rhDAO heparin-binding motif mutants presented herein (patent pending WO2020169577A1)..

  14. Thomas Boehm

    Department of Clinical Pharmacology, Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
    For correspondence
    thomas.boehm@meduniwien.ac.at
    Competing interests
    Thomas Boehm, is named as an inventor with The Medical University of Vienna and the University of Natural Resources and Life Sciences of a patent describing the rhDAO heparin-binding motif mutants presented herein (patent pending WO2020169577A1)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8294-0797

Funding

Austrian Science Fund (T1135)

  • Elisabeth Gludovacz

Sigrid Juséliuksen Säätiö

  • Serhii Vakal
  • Tiina A Salminen

Medicinska Understödsföreningen Liv och Hälsa

  • Serhii Vakal
  • Tiina A Salminen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The experimental protocols for the treatment of rats and mice were approved by the local Animal Welfare Committee and the Federal Ministry of Science, Research and Economy (GZ 66.009/0152-WF/V/3b/2014) and conducted in full accordance with the ARRIVE guidelines.

Copyright

© 2021, Gludovacz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Elisabeth Gludovacz
  2. Kornelia Schuetzenberger
  3. Marlene Resch
  4. Katharina Tillmann
  5. Karin Petroczi
  6. Markus Schosserer
  7. Sigrid Vondra
  8. Serhii Vakal
  9. Gerald Klanert
  10. Jürgen Pollheimer
  11. Tiina A Salminen
  12. Bernd Jilma
  13. Nicole Borth
  14. Thomas Boehm
(2021)
Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
eLife 10:e68542.
https://doi.org/10.7554/eLife.68542

Share this article

https://doi.org/10.7554/eLife.68542

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    Pyrotinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (PERSIST): A multicenter phase II trial

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    Background:

    Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer.

    Methods:

    This multicenter phase II trial was conducted at 23 centers in China. After enrollment, patients received 1 year of extended adjuvant pyrotinib (400 mg/day), which should be initiated within 6 months after the completion of 1-year adjuvant therapy (trastuzumab alone or plus pertuzumab). The primary endpoint was 2-year iDFS rate.

    Results:

    Between January 2019 and February 2022, 141 eligible women were enrolled and treated. As of October 10, 2022, the median follow-up was 24 (interquartile range, 18.0–34.0) months. The 2-year iDFS rate was 94.59% (95% confidence interval [CI]: 88.97–97.38) in all patients, 94.90% (95% CI: 86.97–98.06) in patients who completed 1-year treatment, 90.32% (95% CI: 72.93–96.77) in patients who completed only 6-month treatment, 96.74% (95% CI: 87.57–99.18) in the hormone receptor (HR)-positive subgroup, 92.77% (95% CI: 83.48–96.93) in the HR-negative subgroup, 96.88% (95% CI: 79.82–99.55) in the lymph node-negative subgroup, 93.85% (95% CI: 86.81–97.20) in the lymph node-positive subgroup, 97.30% (95% CI: 82.32–99.61) in patients with adjuvant trastuzumab plus pertuzumab, and 93.48% (95% CI: 86.06–97.02) in patients with adjuvant trastuzumab. The most common adverse events were diarrhea (79.4%), fatigue (36.9%), lymphocyte count decreased (36.9%), nausea (33.3%), and hand-foot syndrome (33.3%).

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    Funding:

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    Clinical trial number:

    ClinicalTrials.gov: NCT05880927

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