- Three scientific articles report how the therapeutic monoclonal antibody Adrecizumab reverses vascular hyperpermeability in sepsis.
- Adrecizumab works by stabilizing the vasoactive peptide hormone adrenomedullin and its redistribution from tissues to blood plasma without blocking adrenomedullin receptor signaling.
- The adcizumab-induced increase in adrenomedullin plasma levels attenuates vascular leakage, improves renal function, and reduces mortality.
- Adrecizumab induces adrenomedullin-mediated stabilization of endothelial barrier function and vascular tone and contributes to the development of septic shock when impaired.
Hennigsdorf/Berlin (Germany) June 14Is, 2018– Adrenomed AG today announces the publication of two groundbreaking documentsSchock[1,2] and a letter to the editor inCriticalCautious who propose a new mode of action of their first adrenomedullin-specific antibody Adrecizumab (HAM8101) in the treatment of sepsis. First author of all articles was Christopher Geven (Department of Intensive Care Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands) in the group of Prof. Peter Picker. Data generated in two animal models of sepsis and in humans with systemic inflammation show that Adrecizumab restores the impaired function of the vascular barrier that causes hemodynamic instability in sepsis and leads to edema formation, organ failure and shock. The story will be the cover of theSchockAugust Number.
Endothelial dysfunction treatment is a completely new causal approach to reduce mortality from sepsis, a disease that affects 24 million people worldwide every year and is currently treated with supportive measures such as vasopressors, organs, etc. To date, there is no treatment to correct endothelial dysfunction, which is also found in other common diseases with high unmet medical needs, such as: B. Heart failure.
Clinical data from over 16,000 patients has shown that the vasoactive peptide hormone adrenomedullin is a key regulator of endothelial integrity. However, because of its short plasma half-life (22 minutes) and its relaxing effect on vascular smooth muscle cells surrounding blood vessels, it has been difficult to target adrenomedullin in a manner that would selectively support its beneficial effects on function. Resistance Based on experimental evidence from preclinical models and two phase I clinical trials, the authors propose a mechanism of action for adcizumab that prevents vasodilation but selectively improves endothelial integrity, resulting in a beneficial effect on hemodynamics and mortality in sepsis:
- Excess Adrecizumab in the blood vessels binds most of the vasoactive peptide 6 kDA adrenomedullin, which diffuses freely between the extravascular and intravascular spaces and anchors it in the intravascular compartment, where it restores endothelial barrier function.
- Adrecizumab in excess does not increase adrenomedullin synthesis in vascular smooth muscle and endothelial cells.
- Adrecizumab (14 days plasma half-life), which binds to N-terminal adrenomedullin, prolongs the short half-life (22 minutes) of the free peptide in the vessels and protects it from N-terminal proteolysis, while only slightly affecting its C-activity binding to the terminal receptor on the endothelium.
- The redistribution of adrenomedullin from the extravascular space to the intravascular compartment promotes the established intravascular effects of adrenomedullin (closure of endothelial lacunae, tight junctions) and at the same time prevents its extravascular effects (vasodilation).
The proposed mode of action is supported by new animal data published in Shock . In a rat endotoxemia model (N=48), administration of Adrecizumab (0.02-2.5 mg/kg HAM8101) prior to induction of bacterial lipopolysaccharide (LPS) sepsis attenuated LPS-induced vascular hyperpermeability by 40-71% compared to controls as measured by renal albumin loss. In a cecal ligation and puncture (CLP) mouse model of sepsis (N=24), a single injection of Adrecizumab (0.1-20 mg/kg) prior to surgical induction of sepsis also significantly reduced albumin leakage into renal tissue (77- 78% versus placebo). At the same time, levels of VEGF, a potent inducer of vascular permeability, were significantly reduced in kidney tissue. In addition, levels of Ang1, a biomarker that improves endothelial barrier function, were elevated. In an additional study in CLP mice (N=60), a single injection of Adrecizumab reduced 7-day mortality by 50%, while repeated injection of the humanized antibody reduced 14-day mortality by 60%. The results provide statistically significant evidence that adcizumab prevents inflammation-related vascular hyperpermeability and improves survival in mouse models of sepsis.
"Endothelial dysfunction and vasodilation are hallmarks of sepsis," commented Dr. Andreas Bergmann, Founder and Chief Scientific Officer of Adrenomed AG. "Adrecizumab's unique mode of action has great potential to add significant benefits to the treatment of sepsis and early septic shock."
4Q/2018. In addition, Adrenomed is planning a phase II proof-of-concept study in patients with acute congestive heart failure.
Adrenomed AG is a privately held biopharmaceutical company headquartered in Hennigsdorf near Berlin, Germany, with a clear mission to improve survival by improving vascular integrity in critically ill patients. Its lead candidate, Adrecizumab, a monoclonal antibody therapy targeting the vasoactive adrenomedullin system, is in clinical trials for early septic shock. Impaired vascular integrity is a pathology that occurs in a variety of diseases. Another indication besides sepsis and early septic shock is acute decompensated heart failure.
Adrenomedullin is a potent vasoregulatory hormone released by endothelial and smooth muscle cells. It is a key regulator of blood pressure and vascular tone and plays a crucial role in the development of septic shock.
Adrecizumab is a humanized monoclonal antibody specific for adrenomedullin and has been patented as a first-in-class therapy for the treatment and prevention of compromised vascular integrity that is a hallmark of septic shock. Adrecizumab has demonstrated excellent safety and tolerability and high efficacy in a variety of preclinical animal models, mimicking standard care in the intensive care unit. In several resuscitated models of vascular integrity (mouse, rat, pig), adcizumab reduced vascular leakage, stabilized circulation by restoring blood pressure, normalized fluid balance and reduced the need for vasopressors, improved renal function, and reduced mortality from septic shock at 50 %. The excellent tolerability and safety of Adrecizumab was confirmed in two phase I clinical trials in healthy volunteers with and without LPS exposure. Adrecizumab is currently being evaluated in a Phase II, double-blind, placebo-controlled, randomized, multi-center, proof-of-concept, dose-ranging study of two doses of ADRECIZUMAB in patients with early-stage septic shock and plasma concentrations of Bio-ADM with income > 70 pg/mL (AdrenOSS- 2, ClinicalTrials.gov identifier: NCT03085758).
is defined as life-threatening organ dysfunction due to a dysregulated host response to a proven or suspected infection resulting in a fall in mean arterial pressure (MAP) < 65 mmHg that is contradictory to fluid therapy and requires vasopressors. Refractory to volume resuscitation is defined as non-response to administration of 30 mL of fluid per kilogram of body weight or inadequate hemodynamic results as determined by physician assessment.
About animal models for sepsis
In the cecal ligation and puncture (CLP) model, peritonitis is surgically induced by ligating the cecum and puncturing it with a tiny needle. The contents of the cecum are then pressed through the wound.
In the endotoxemia model, mice were injected with 5 mg/kg bacterial lipopolysaccharide (LPS).
- Geven C, Bergmann A, Kox M, Pickkers P. Vascular effects of adrenomedullin and the anti-adrenomedullin antibody adrecizumab in sepsis. Shock 2018 post ahead of print
- Geven C, Peters E, Schroedter M, Struck J, Bergmann A, McCook O, et al. Effects of the humanized anti-adrenomedullin antibody Adrecizumab (HAM8101) on vascular barrier function and survival in rodent models of systemic inflammation and sepsis. shock 2018; Publish before printing
- Geven C and Pickkers P. The mechanism of action of Adrecizumab antibody binding to adrenomedullin. intensive care unit 2018; 22:159
Frauke Hein, Ph.D. (OBC)
Phone: +49 (0)3302 2077814
Adrecizumab acts through stabilization of the vasoactive peptide hormone adrenomedullin and its redistribution from tissue into blood plasma without blocking adrenomedullin receptor signaling.What are the effects of Adrenomedullin? ›
Adrenomedullin is an important peptide hormone involved in sepsis. Its effects include vasodilation, stabilization of the endothelial barrier, and immunoregulation. Administration of ADM in animal models of inflammation, organ injury, and infection resulted in improved outcome.What is Adrenomedullin in sepsis? ›
Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality.Is adrenomedullin a hormone? ›
The peptide hormone adrenomedullin (ADM) consists of 52 amino acids and plays a pivotal role in the regulation of many physiological processes, particularly those of the cardiovascular and lymphatic system.Where is Adrenomedullin produced? ›
Adrenomedullin is a member of the calcitonin family of peptides. It is produced by vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, adrenal chromaffin cells, macrophages, bronchial epithelium, and many other cell types.How is sepsis cured? ›
Healthcare professionals should treat sepsis with antibiotics as soon as possible. Antibiotics are critical tools for treating life-threatening infections, like those that can lead to sepsis.What is the difference between sepsis and sepsis syndrome? ›
Sepsis is the systemic response to severe infection in critically ill patients. Sepsis, sepsis syndrome, and septic shock represent the increasingly severe stages of the same disease.Can sepsis heal? ›
Most people make a full recovery from sepsis. But it can take time. You might continue to have physical and emotional symptoms. These can last for months, or even years, after you had sepsis.What receptors does Adrenomedullin have? ›
Adrenomedullin (AM) has two specific receptors formed by the calcitonin-receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3. These are known as AM1 and AM2 receptors, respectively. In addition, AM has appreciable affinity for the CGRP1 receptor, composed of CL and RAMP1.What is Adrenomedullin level? ›
Adrenomedullin (AM) is a blood pressure-lowering peptide expressed in the cardiovascular tissues including the vascular wall and heart. Plasma levels of AM are elevated in patients with hypertension, heart failure or arteriosclerosis, as compared with control subjects.
Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in human pheochromocytoma tissue. AM and AM gene expression are widely distributed in the cardiovascular system, including the kidney.What is Adrenomedullin in heart failure? ›
Adrenomedullin is an endogenous hormone that is released as a counteracting response to volume overload. Levels of ADM are clearly increased in patients with heart failure, and higher levels are related to more advanced heart failure and worse outcomes.What does the CGRP protein do? ›
CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways.What is the structure of Adrenomedullin? ›
Adrenomedullin, a hypotensive peptide found in human pheochromocytoma, consists of 52 amino acids, has 1 intramolecular disulfide bond, and shows slight homology with the calcitonin gene-related peptide (CGRP; 114130).What is plasma adrenomedullin? ›
Adrenomedullin is a novel vasorelaxant peptide recently isolated from pheochromocytoma. 1. Ichiki et al13 and Nishikimi et al14 have demonstrated that this peptide is present not only in human adrenal medulla but also in human plasma.What is bio Adrenomedullin? ›
Adrenomedullin (ADM or AM) is a vasodilator peptide hormone of uncertain significance in human health and disease. It was initially isolated in 1993 from a pheochromocytoma, a tumor of the adrenal medulla: hence the name.