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

E. Gludovacz, K. Schuetzenberger, M. Resch, K. Tillmann, K. Petroczi, M. Schosserer, S. Vondra, S. Vakal, G. Klanert, J. Pollheimer, T.A. Salminen, B. Jilma, N. Borth, T. Boehm

Tutkimustuotos: LehtiartikkeliArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.
AlkuperäiskieliEnglanti
JulkaisueLife
Vuosikerta10
DOI - pysyväislinkit
TilaJulkaistu - 2021
OKM-julkaisutyyppiA1 Julkaistu artikkeli, soviteltu

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