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Effects of the Humanized Anti-Adrenomedullin Antibody Adrecizumab (HAM8101) on Vascular Barrier Function and Survival in Rodent Models of Systemic Inflammation and Sepsis

Geven, Christopher*; Peters, Esther; Schroedter, Mathias; Struck, Joachim; Bergmann, Andreas; McCook, Oscar§; Radermacher, Peter§; Kox, Matthijs*; Pickkers, Peter*

doi: 10.1097/SHK.0000000000001102
Basic Science Aspects
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Purpose: Adrenomedullin (ADM) is an important regulator of endothelial barrier function during sepsis. Administration of a murine antibody targeted against the N-terminus of ADM (HAM1101) resulted in improved outcome in models of murine sepsis. We studied the effects of a humanized form of this antibody (HAM8101, also known as Adrecizumab) on vascular barrier dysfunction and survival in rodent models of systemic inflammation and sepsis.

Methods: Rats (n=48) received different dosages of HAM8101 or placebo (n = 8 per group), directly followed by administration of lipopolysaccharide (5 mg/kg). Twenty-four hours later, Evans Blue dye was administered to assess vascular leakage in kidney and liver tissue. Furthermore, mice (n = 24) were administered different dosages of HAM8101 or placebo (n = 6 per group), immediately followed by cecal ligation and puncture (CLP). Eighteen hours later, albumin, vascular endothelial growth factor (VEGF), and angiopoietin-1 were analyzed in the kidney. Finally, effects of single and repeated dose administration of HAM1101, HAM8101 and placebo on survival were assessed in CLP-induced murine sepsis (n = 60, n = 10 per group).

Results: Dosages of 0.1 and 2.5 mg/kg HAM8101 attenuated renal albumin leakage in endotoxemic rats. Dosages of 0.1, 2.0, and 20 mg/kg HAM8101 reduced renal concentrations of albumin and the detrimental protein VEGF in septic mice, whereas concentrations of the protective protein angiopoietin-1 were augmented. Both single and repeated administration of both HAM1101 and HAM8101 resulted in improved survival during murine sepsis.

Conclusions: Pretreatment with the humanized anti-ADM antibody HAM8101 improved vascular barrier function and survival in rodent models of systemic inflammation and sepsis.

*Department of Intensive Care Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands

Department of Intensive Care Medicine, Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands

Adrenomed AG, Hennigsdorf, Germany

§Institute of Anesthesiological Pathophysiology and Process Engineering, University Hospital Ulm, Ulm, Germany

Address reprint requests to Peter Pickkers, MD, PhD, Radboud University Medical Center, Department of Intensive Care Medicine (710), PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: peter.pickkers@radboudumc.nl

Received 3 November, 2017

Revised 21 November, 2017

Accepted 4 January, 2018

Study protocol approval was obtained from the appropriate governing institutes (approval numbers: Preclinics: 2347-35-2015 issued by Landesamt für Umwelt, Gesundheit und Verbraucherschutz Brandenburg; Phenos: 33.9-42502-04-12/0846 issued by Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit).

The dataset used and analyzed during the current study is available from the corresponding author on reasonable request.

MS, JS, and AB are employed by Adrenomed AG and hold shares in Adrenomed AG. PP received travel reimbursements and consultancy fees from Adrenomed. PP's institution received a research grant from Adrenomed AG. PR received an unrestricted Research grant and travel reimbursements from Adrenomed AG. CG, OM, MK, and EP declare to have no competing interests. Adrenomed AG holds patent rights on ADM antibodies.

This project was financed by funds of Adrenomed AG and the German Ministry of Research and Education (bmbf) under grant number 031A515.

The authors report no conflicts of interest.

© 2018 by the Shock Society