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

eLife

Katharina Tillmann¹  Kornelia Schuetzenberger²  Nicole Borth³  Gerald Klanert³  Markus Schosserer³  Elisabeth Gludovacz⁴  Marlene Resch⁵  Bernd Jilma⁵  Thomas Boehm⁵  Karin Petroczi⁵  Sigrid Vondra⁶  Jürgen Pollheimer⁶  Tiina A Salminen⁷  Serhii Vakal⁷ 

[1] Center for Biomedical Research, Medical University of Vienna, Vienna, Austria;Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria;Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria;Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria;Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria;Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria;Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria;Strutural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland;

关键词: diamine oxidase;    histamine;    heparin;    heparan sulfate proteoglycan;    clearance;    half-life;    Mouse;    Rat;    Other;   

DOI  :  10.7554/eLife.68542

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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).

【 授权许可】

CC BY