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

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 str...

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Autores principales:	Elisabeth Gludovacz, Kornelia Schuetzenberger, Marlene Resch, Katharina Tillmann, Karin Petroczi, Markus Schosserer, Sigrid Vondra, Serhii Vakal, Gerald Klanert, Jürgen Pollheimer, Tiina A Salminen, Bernd Jilma, Nicole Borth, Thomas Boehm
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	diamine oxidase histamine heparin heparan sulfate proteoglycan clearance half-life Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d7281aa1f5af4be284b2a714515c12fb
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spelling	oai:doaj.org-article:d7281aa1f5af4be284b2a714515c12fb2021-11-25T12:30:56ZHeparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical10.7554/eLife.685422050-084Xe68542https://doaj.org/article/d7281aa1f5af4be284b2a714515c12fb2021-09-01T00:00:00Zhttps://elifesciences.org/articles/68542https://doaj.org/toc/2050-084XBackground: 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. Methods: Positively charged amino acids of the heparin-binding motif of hDAO were replaced with polar serine or threonine residues. Binding to heparin and heparan sulfate, cellular internalization and clearance in rodents were examined. Results: Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After mutation of the heparin-binding motif, 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); Sigrid Juselius Foundation, Medicinska Understödsförening Liv och Hälsa rft (TAS and SeV).Elisabeth GludovaczKornelia SchuetzenbergerMarlene ReschKatharina TillmannKarin PetrocziMarkus SchossererSigrid VondraSerhii VakalGerald KlanertJürgen PollheimerTiina A SalminenBernd JilmaNicole BorthThomas BoehmeLife Sciences Publications Ltdarticlediamine oxidasehistamineheparinheparan sulfate proteoglycanclearancehalf-lifeMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	diamine oxidase histamine heparin heparan sulfate proteoglycan clearance half-life Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	diamine oxidase histamine heparin heparan sulfate proteoglycan clearance half-life Medicine R Science Q Biology (General) QH301-705.5 Elisabeth Gludovacz Kornelia Schuetzenberger Marlene Resch Katharina Tillmann Karin Petroczi Markus Schosserer Sigrid Vondra Serhii Vakal Gerald Klanert Jürgen Pollheimer Tiina A Salminen Bernd Jilma Nicole Borth Thomas Boehm Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
description	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. Methods: Positively charged amino acids of the heparin-binding motif of hDAO were replaced with polar serine or threonine residues. Binding to heparin and heparan sulfate, cellular internalization and clearance in rodents were examined. Results: Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After mutation of the heparin-binding motif, 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); Sigrid Juselius Foundation, Medicinska Understödsförening Liv och Hälsa rft (TAS and SeV).
format	article
author	Elisabeth Gludovacz Kornelia Schuetzenberger Marlene Resch Katharina Tillmann Karin Petroczi Markus Schosserer Sigrid Vondra Serhii Vakal Gerald Klanert Jürgen Pollheimer Tiina A Salminen Bernd Jilma Nicole Borth Thomas Boehm
author_facet	Elisabeth Gludovacz Kornelia Schuetzenberger Marlene Resch Katharina Tillmann Karin Petroczi Markus Schosserer Sigrid Vondra Serhii Vakal Gerald Klanert Jürgen Pollheimer Tiina A Salminen Bernd Jilma Nicole Borth Thomas Boehm
author_sort	Elisabeth Gludovacz
title	Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
title_short	Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
title_full	Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
title_fullStr	Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
title_full_unstemmed	Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
title_sort	heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/d7281aa1f5af4be284b2a714515c12fb
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Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical

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