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

Abstract

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

Massive release of TH2 cytokines induced a cytokine storm during a severe mast cell activation event in a patient with indolent systemic mastocytosis

“…The strong correlations of histamine and cytokine concentrations and clinical symptoms with a clear clinical improvement after histamine concentrations dropped significantly after the peak suggest that recombinant human diamine oxidase be used to rapidly remove histamine and anti-IL-6 and anti-IL-5 biologicals be used to mitigate the severity of acute MCA events. 7,37 Double-blind randomized controlled studies during severe acute MCA attacks will be almost impossible to perform in mastocytosis or MCAS patients, and recombinant human diamine oxidase is not available, but IL-5 and IL-6 blocking reagents have been approved and might show significant clinical benefits in severe life-threatening T H 2 cytokine-driven MCA events.…”

Toward Oral Supplementation of Diamine Oxidase for the Treatment of Histamine Intolerance

“…Besides the approach of an oral DAO supplementation aiming to degrade histamine in the intestine, another working group focused on the development of a first-in-class histaminedegrading biopharmaceutical for histamine regulation in the peripheral blood [37]. Here, a recombinantly produced human DAO was mutated in its heparin-binding motif to decrease its plasma clearance.…”

Usefulness of DAO biomarker in difficult allergy. Consideration based on own typical cases

“…Biogenna histamina (2-[4-imidazolilo]etyloamina) jest przechowywana przez bazofile oraz komórki tuczne i może być szybko uwalniana po stymulacji z wewnątrzkomórkowych pęcherzyków spichrzowych. Nadmierne stężenie histaminy w osoczu powoduje objawy zespołu aktywacji komórek tucznych, mastocytozy lub anafilaksji [2]. Po aktywacji receptorów histaminowych 1 i 2 działa ona głównie na komórki śródbłonka naczyniowego, oskrzeli i mięśni gładkich, wpływa na układ sercowo-naczyniowy, skórę oraz przewód pokarmowy i oddechowy [3].…”

“…Po aktywacji receptorów histaminowych 1 i 2 działa ona głównie na komórki śródbłonka naczyniowego, oskrzeli i mięśni gładkich, wpływa na układ sercowo-naczyniowy, skórę oraz przewód pokarmowy i oddechowy [3]. Leki przeciwhistaminowe są często niewystarczająco skuteczne [2]. Pierwsze naukowe odniesienia do NH pochodzą z ubiegłego wieku, lecz prawie 80% to prace z ostatniej dekady, co odzwierciedla rosnące zainteresowanie badaczy omawianym zaburzeniem [4].…”

“…Poza od dawna znanym i szeroko stosowanym naturalnym suplementem DAO z nerek wieprzowych (DAOpro) trwają intensywne programy biotechnologiczne nad uzyskaniem rekombinowanego enzymu (np. rhDAO z hodowli komórek chomika) lub DAO-1 z drożdży Yarrowia lipolytica [2,36].…”