PB1037 - Recombinant human diamine oxidase prevents pulmonary haemorrhage and improves oxygenation in histamine induced shock

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

MW

Matthias Weiss-Tessbach

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

Co-Author(s)

MR

Marlene Rager-Resch

Veterinarian
Department of Clinical Pharmacology, Medical University Vienna
Vienna, Wien, Austria
BR

Birgit Reiter

Medical Doctor
Department of Laboratory Medicine, Medical University Vienna
Vienna, Wien, Austria
FK

Felix Kosta

PhD Student
Department of Clinical Pharmacology, Medical University Vienna
Vienna, Wien, Austria
MM

Martin Murauer

PhD Student
Department of Clinical Pharmacology, Medical University Vienna
Vienna, Wien, Austria
EG

Elisabeth Gludovacz

Post Doc
Department of Biotechnology, University of Natural Resources and Life Sciences
Vienna, Wien, Austria
TB

Thomas Boehm

Post Doc
Department of Clinical Pharmacology, Medical University Vienna
Vienna, Wien, Austria
Bernd Jilma, MD

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

Background: Anaphylaxis, a potentially life-threatening systemic reaction, induces histamine release by mast cells and basophils, which increases vasodilation and vascular permeability inducing shock, and enhances tissue factor expression potentially leading to disseminated intravascular coagulation (Gelbenegger 2023). Adrenaline, an unproven but guideline-recommended treatment for anaphylaxis, can induce serious adverse events like lung oedema (Cervellin 2016). Diamine oxidase (DAO), a histamine-degrading enzyme, demonstrated beneficial effects on hemodynamic parameters in animal models (Karer 2022, Weiss-Tessbach 2023).

Aims: This study investigated the effects of recombinant human DAO with a mutated heparin binding motif (rhDAO_HBM) on vital parameters and partial oxygen pressure in a guinea pig model.

Methods: Guinea pigs, the only histamine-sensitive rodent species, received a subcutaneous injection of 1mg/kg histamine to simulate peripheral histamine release, and received oxygen intranasally. They were treated with intravenous rhDAO_mHBM (4 or 8mg/kg) or intramuscular adrenaline (5µg/kg). Partial oxygen pressure was measured to quantify oxygen uptake. Outcome parameters included shock prevention and oxygenation.

Results: Subcutaneous injection of histamine induced shock within 6 minutes. Therapeutic use of 5µg/kg adrenaline, a similar dosage to human auto-injectors, neither prevented shock nor lung haemorrhage (Fig. 1). In contrast, rhDAO_mHBM prevented hemodynamic shock and lung bleeding. Prophylactic rhDAO_mHBM mitigated the decrease in partial oxygen pressure from baseline to minute 60 compared to no treatment (72% lower; p=0.03) or adrenaline (75% lower; p=0.001) demonstrating better oxygenation.

Conclusion(s): rhDAO_mHBM is the first specific therapy to effectively counteract massive histamine release encountered in human anaphylaxis (vanderLinden 1992); it prevented lung bleeding, improved oxygenation and prevented haemodynamic shock. In contrast, intramuscular adrenaline neither prevented shock, nor lung haemorrhage associated de-oxygenation. These pre-clinical results further support clinical development of rhDAO_mHBM in various indications.