The biogenic amine histamine (2-[4-imidazolyl]ethylamine) is stored by basophils and mast cells (MCs) and is rapidly released after stimulation from intracellular storage vesicles. Following activation of the histamine receptors 1 and 2, histamine acts mainly on vascular endothelial, bronchial, and smooth muscle cells and causes symptoms affecting the cardiovascular system, the skin, and the gastrointestinal and respiratory tracts (Jutel et al., 2009; Valent et al., 2011). It induces nitric oxide synthesis, which causes vasodilation, vascular hyperpermeability, edema formation, and consequently hypotension (Ashina et al., 2015; Claesson-Welsh, 2015; Pober and Sessa, 2015; Valent et al., 2019). The development of hypotension strongly correlates with histamine concentrations (Kaliner et al., 1982). Multiple potentially life-threatening conditions such as mast cell activation syndrome (MCAS) or anaphylaxis are accompanied by elevated histamine levels (Valent et al., 2011). In severe anaphylaxis, mean histamine concentrations of 140 ng/mL have been measured (van der Linden et al., 1992).

The copper-containing amine oxidase human diamine oxidase (hDAO; E.C. 1.4.3.6) is a homodimer encoded by the AOC1 gene (Barbry et al., 1990; Chassande et al., 1994), which is highly expressed in the intestine (Wollin et al., 1998), the kidneys (Schwelberger et al., 1998), and extravillous trophoblasts (Velicky et al., 2018). In pregnancy serum, hDAO at a mean concentration of 125 ng/mL rapidly degraded 100 ng/mL histamine with a half-life of 3.4 min (Boehm et al., 2019). In the 1930s, porcine diamine oxidase was already used to treat histamine-related pathologies with limited success (Laymon and Cumming, 1939; Miller and Piness, 1940). After intravenous infusion of recombinant hDAO (rhDAO) in rats and mice, the half-life was less than 5 min (Gludovacz et al., 2020). The rapid clearance was not caused by binding of the N-glycans to the asialoglycoprotein- or the mannose-receptor. Diamine oxidase did not only bind to but was also internalized by various epithelial and endothelial cell lines. Internalization was inhibited by high molecular weight heparin (HMWH), and glycosaminoglycan- and heparan sulfate (HS)-deficient CHO cell lines were incapable of rhDAO uptake. Diamine oxidase is produced by intestinal and proximal tubular kidney epithelial cells and binds to the basolateral membranes in the lamina propria after secretion into the interstitial compartment and in vitro also to endothelial cells (Schwelberger et al., 1999; Wollin et al., 1998). It is released from its binding sites by heparin infusion, resulting in an increase in plasma activity (Biebl et al., 2002; D’Agostino et al., 1989; Gäng et al., 1975; Hansson and Thysell, 1973; Klocker et al., 2004; Klocker et al., 2000). Robinson-White et al. described the binding of rat placental DAO to rat and guinea pig microvascular endothelial cells and its displacement by heparin, indicating that DAO binds to cell surface heparan sulfate proteoglycans (HSPG) (Robinson-White et al., 1985). During anaphylaxis, secretion of heparin from MCs likely results in DAO release from HSPG located in the extracellular matrix or on the surface of gastrointestinal epithelial cells (Boehm et al., 2019). Cell surface HSPG probably mediate cellular binding and/or uptake of rhDAO.

Novotny et al., 1994 proposed that the amino acids 568–575 or RFKRKLPK constitute a heparin-binding motif (HBM) (Novotny et al., 1994). These amino acid stretches form a ring-like structure including the motifs of both monomers on the surface of DAO (McGrath et al., 2009). No negatively charged amino acids are close to this positively charged ring structure (McGrath et al., 2009). The putative heparin-binding site of hDAO possesses the size, shape, and electrostatic properties suitable for heparin and HS binding (Gludovacz et al., 2020). However, it has never been demonstrated, neither in vitro nor in vivo, that the RFKRKLPK sequence mediates heparin and HS binding.

The short half-life of rhDAO in rats and mice is highly unfavorable for the development of rhDAO as a new treatment option for diseases with rapid and excessive histamine release from MCs or basophils. We herein demonstrate for the first time that rhDAO rapidly degrades pathophysiologically relevant histamine concentrations. Using appropriate mutations in the RFKRKLPK sequence, we prove the heparin binding function of this ring structure motif and its involvement in the ultra-rapid plasma clearance of rhDAO. The HBM mutants show a strongly decreased binding to heparin and HS, minimal cellular internalization, and a strong reduction of the in vivo clearance in rodents with unchanged catalytic activity. This study provides promising data for the development of rhDAO as a first-in-class biopharmaceutical for the treatment of conditions with elevated systemic histamine concentrations.

Plasma histamine concentrations of at least 500 ng/mL (4.5 µM) were measured in a systemic mastocytosis patient following gastrointestinal endoscopy (Desborough et al., 1990). We recently published data on the circulatory collapse in a mastocytosis patients with 70 ng/mL plasma histamine (Boehm et al., 2019). Histamine concentrations in another systemic mastocytosis patient increased from 10 ng/mL to 35 ng/mL over a few hours. The patient developed severe clinical symptoms despite high-dose treatment with the histamine receptor 1 antagonist diphenhydramine and the histamine receptor 2 antagonist ranitidine (Boehm et al., 2019). Despite treatment with histamine receptor antagonists up to four times the approved dose and the use of additional medications, approximately 70% of mastocytosis patients define themselves as disabled in accordance with standard definitions of disability (Hermine et al., 2008). Finally, 25–33% of chronic urticaria patients are resistant to histamine receptor antagonists (van den Elzen et al., 2017). Why is the efficacy of histamine receptor blockers during severe anaphylaxis, MC activation, or chronic urticaria limited?

Kaliner et al., 1982 and Owen et al., 1982 described that in healthy volunteers two combinations of histamine receptor antagonists, cimetidine with hydroxyzine and cimetidine with chlorpheniramine, respectively, were only able to sufficiently block symptom development until systemic histamine concentrations of approximately 6 ng/mL were reached. Single treatments with either histamine receptor 1 or 2 antagonist were minimally protective. The 6 ng/mL threshold is only three to four times higher compared to no treatment and 20-fold below the mean histamine concentration of 140 ng/mL reached during severe anaphylaxis after an insect sting challenge (van der Linden et al., 1992). Clinically relevant hypotension starts to develop at levels above 5 ng/mL histamine. We can only conclude that histamine receptor antagonists are easily overwhelmed during anaphylaxis, MC activation, and even chronic urticaria.

Herein we show for the first time that rhDAO can rapidly and completely degrade pathophysiologically relevant histamine concentrations of 100 ng/mL. Nevertheless, in rodents wildtype rhDAO showed a very fast α-distribution half-life, rendering it unsuitable for further development as a new and first-in-class biopharmaceutical. The fast clearance in vivo was independent of the asialoglycoprotein- and mannose-receptors, the two well-characterized protein clearance systems. Cellular internalization in vitro into various cell lines was dependent on the interaction with HS glycosaminoglycans and was blocked by excess heparin (Gludovacz et al., 2020).

We therefore mutated the putative HBM (Novotny et al., 1994) and unequivocally demonstrated that this 2 × 8 linear amino acid stretch, which forms a distinct positively charged ring structure, mediates not only cellular internalization but also rapid clearance in rodents. Mutations in the HBM eliminated heparin binding. Importantly, DAO activity of wildtype and various mutants was indistinguishable. The wildtype DAO dimer sequence excluding the HBM contains 84 arginine and 42 lysines residues, many of which are surface-exposed, but none of these positively charged residues seems critically involved in heparin binding. BLAST analysis of the RFKRKLPK motif revealed a high sequence identity of R568 and K575 in all mammalian DAO sequences analyzed. Our experimental data suggest the essential role of the conserved R568 residue in the heparin binding of DAO, which is supported by the in silico modeling comparing the interactions of wildtype and mutant DAO with the docked heparin hexasaccharide. While the single mutation of this amino acid was sufficient to achieve a comparable decrease in binding to heparin-sepharose versus the double mutants, a strong reduction of cellular uptake was only accomplished with the double mutants. Neither ITC nor BLI detected any interaction of rhDAO-R568S/R571T with HMWH and HS. In silico modeling supports not only the biochemical and cellular in vitro but also the rats and mice in vivo data. The HBM mutant with the best in vivo pharmacokinetic profile, rhDAO-R568S/R571T, showed low increases in the Gibbs free energy concerning stability but demonstrated a strong decrease in affinity. The correlation coefficient comparing in silico-estimated affinity data changes with experimental heparin-sepharose in vitro binding data of wildtype and four HBM mutants is 0.93 with a p-value of less than 0.01.

Incubation of various cell lines with rhDAO-R568S/R571T did not completely abrogate cellular uptake, but flow cytometry and western blot analyses showed that at least 15% of the internalization cannot be attributed to HSPG interaction. This is in accordance with our previous study, where a 100-fold excess of HMWH over rhDAO-WT could not reduce the uptake below 5 and 25% in various cell lines (Gludovacz et al., 2020). In the same study, we observed the presence of high-affinity-binding sites in HUVEC/TERT2 cells in addition to the low-affinity HSPG-binding sites. Similarly, cellular binding of amyloid protein precursor and fibroblast growth factor 2 is predominantly mediated by low-affinity HSPG interactions that serve as scaffolds or co-receptors that promote and/or stabilize the formation of complexes of proteins and high-affinity receptors (Duchesne et al., 2012; Reinhard et al., 2013; Thompson et al., 1994; Xu and Esko, 2014). Since the HS-binding sites can outnumber the amount of protein-specific receptors by 100- to 1000-fold (Duchesne et al., 2012), it is not surprising that only a low proportion of binding can be attributed to the latter. These high-affinity-binding sites might be responsible for the β-elimination of the heparin-binding mutants. Our data are in agreement with this hypothesis. While the clearance of more than 90% of the rhDAO-WT dose in the fast α-elimination phase of less than 5 min is fully abrogated by the double mutation of R568 and R571, the long β-elimination phase of about 6 hr is more or less unchanged. It is therefore likely that this second phase is determined by a different clearance mechanism independent of the heparin-binding domain.

It will be interesting to study the distribution of wildtype versus HBM mutant DAO variants after intravenous infusion in animal models because it is not clear which cells or organs remove 90% of the wildtype DAO protein within a few minutes. The liver has been considered mainly responsible for elimination of DAO, but in view of the dependence of DAO internalization on HS, endothelial cells throughout the circulatory system could rapidly remove DAO (D’Agostino et al., 1986). These cells abundantly express HSPGs and are able to bind and internalize DAO in vitro (Fuster and Wang, 2010; Gludovacz et al., 2020).

The half-life of the HBM mutant rhDAO-R568S/R571T is approximately 6 hr in rodents, which is certainly sufficient for the treatment of most human anaphylaxis events. The rodent HBM does not contain the central ⁵⁷⁰KRK⁵⁷² sequence present in humans but instead ⁵⁷⁰GQT⁵⁷² and therefore the half-life in humans could be longer, assuming that the 6 hr half-life is still at least partially determined by the same HS internalization process. The rodent HBM is only weakly heparin binding.

In conclusion, mutations in the proposed and now proven HBM converted rhDAO wildtype protein into a candidate for a first-in-class histamine receptor-independent biopharmaceutical for the rapid and complete elimination of excessive histamine. First clinical indications might be diseases where it has been known for decades that histamine plays an important pathophysiological role. These include anaphylaxis, MC activation syndrome, mastocytosis, and chronic urticaria. Nevertheless, the use of HBM mutants will also allow clinical proof-of-concept studies in other diseases, where the involvement of histamine and MCs is suspected, but where clinical studies with available histamine receptor antagonists were unsuccessful. No drug blocking histamine receptor 4 has been approved to date. This group of diseases includes, amongst others, asthma, atopic dermatitis, infusion reactions, different forms of pruritus, and inflammatory bowel disease. rhDAO with HBM mutations might overcome the current limitations of histamine receptor antagonists for the treatment of diseases that lead to life-threatening histamine exposure but are resistant to conventional treatment modalities.

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.

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Author details

1. Elisabeth Gludovacz

   1. Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria
   2. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing – review and editing

   Competing interests

   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)

   "This ORCID iD identifies the author of this article:" 0000-0002-1837-2422

2. Kornelia Schuetzenberger

   Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria

   Contribution

   Investigation, Methodology

   Competing interests

   none

3. Marlene Resch

   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

   Contribution

   Investigation, Methodology

   Competing interests

   None

4. Katharina Tillmann

   Center for Biomedical Research, Medical University of Vienna, Vienna, Austria

   Contribution

   Investigation, Methodology

   Competing interests

   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)

5. Karin Petroczi

   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

   Contribution

   Investigation

   Competing interests

   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)

6. Markus Schosserer

   Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria

   Contribution

   Investigation

   Competing interests

   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)

   "This ORCID iD identifies the author of this article:" 0000-0003-2025-0739

7. Sigrid Vondra

   Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria

   Contribution

   Investigation, Methodology

   Competing interests

   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)

8. Serhii Vakal

   Strutural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

   Contribution

   Investigation, Methodology, Visualization, Writing – review and editing

   Competing interests

   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)

9. Gerald Klanert

   Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria

   Contribution

   Investigation, Validation

   Competing interests

   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)

10. Jürgen Pollheimer

    Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria

    Contribution

    Writing – review and editing

    Competing interests

    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)

    "This ORCID iD identifies the author of this article:" 0000-0001-8440-5221

11. Tiina A Salminen

    Strutural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

    Contribution

    Investigation, Methodology, Visualization, Writing – review and editing

    Competing interests

    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)

12. Bernd Jilma

    Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

    Contribution

    Conceptualization, Funding acquisition, Supervision, Writing – review and editing

    Competing interests

    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, University of Natural Resources and Life Sciences, Vienna, Austria

    Contribution

    Funding acquisition, Supervision, Writing – review and editing

    Competing interests

    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, Medical University of Vienna, Vienna, Austria

    Contribution

    Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing – review and editing

    For correspondence

    thomas.boehm@meduniwien.ac.at

    Competing interests

    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)

    "This ORCID iD identifies the author of this article:" 0000-0002-8294-0797

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