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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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 \u03b1-distribution half-life of the wildtype protein was eliminated, and the clearance was significantly reduced in rodents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>Austrian Science Fund (FWF) Hertha Firnberg program grant T1135 (EG); Sigrid Juselius Foundation, Medicinska Underst\u00f6dsf\u00f6rening Liv och H\u00e4lsa rft (TAS and SeV).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.68542","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T08:03:48Z","timestamp":1630569828000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.68542","source":"Crossref","is-referenced-by-count":16,"title":["Heparin-binding motif mutations of human diamine oxidase allow the development of a first-in-class histamine-degrading biopharmaceutical"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1837-2422","authenticated-orcid":true,"given":"Elisabeth","family":"Gludovacz","sequence":"first","affiliation":[{"name":"Department of Biotechnology, University of Natural Resources and Life Sciences","place":["Vienna, Austria"]},{"name":"Department of Clinical Pharmacology, Medical University of Vienna","place":["Vienna, 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