Vascular Effects of Adrenomedullin and the Anti-Adrenomedullin Antibody Adrecizumab in Sepsis

Abstract

Sepsis remains a major scientific and medical challenge, for which, apart from significant refinements in supportive therapy, treatment has barely changed over the last few decades. During sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock. The free circulating peptide adrenomedullin (ADM) is involved in the regulation of the endothelial barrier function and tone of blood vessels. Several animal studies have shown that ADM administration improves outcome of sepsis. However, in higher dosages, ADM administration may cause hypotension, limiting its clinical applicability. Moreover, ADM has a very short half-life and easily adheres to surfaces, further hampering its clinical use. The non-neutralizing anti-ADM antibody Adrecizumab (HAM8101) which causes a long-lasting increase of plasma ADM has shown promising results in animal models of systemic inflammation and sepsis; it reduced inflammation, attenuated vascular leakage, and improved hemodynamics, kidney function, and survival. Combined with an excellent safety profile derived from animal and phase I human studies, Adrecizumab represents a promising candidate drug for the adjunctive treatment of sepsis. In this review, we first provide a brief overview of the currently available data on the role of adrenomedullin in sepsis and describe its effects on endothelial barrier function and vasodilation. Furthermore, we provide a novel hypothesis concerning the mechanisms of action through which Adrecizumab may exert its beneficial effects in sepsis.

Safety, tolerability and pharmacokinetics/pharmacodynamics of the adrenomedullin antibody adrecizumab in a first‐in‐human study and during experimental human endotoxaemia in healthy subjects

“…Our data revealed dose‐proportional maximum concentrations of adrecizumab which were reached almost immediately after cessation of study drug infusion, a low V z , low CL and a long T ½λ . Moreover, adrecizumab infusion induced a rapid and profound dose‐dependent increase in its target peptide ADM, which is thought to explain its mechanism of action . Adrecizumab did not affect vital signs or cytokine Cl, although it did result in a swifter resolution of flu‐like symptoms in the human endotoxaemia study.…”

Adrenomedullin in heart failure: pathophysiology and therapeutic application

“…Currently, adrecizumab is being evaluated in a phase II trial in human septic shock (http://clinicaltrials.gov identifier: NCT03085758). There were no safety concerns observed in pre‐clinical studies, as well as in two phase I studies in which 0.5, 2 and 8 mg/kg were administered to healthy volunteers . Importantly, even though adrecizumab induced great increases in circulating levels of ADM, this did not cause hypotension.…”

“…Because adrecizumab is a non‐neutralizing antibody, the net effect is a significant increase of functional plasma ADM which leads to – as we hypothesize – the restoration of vascular integrity (endothelial effect) and less vasodilatation (vascular smooth muscle cell effect due to decreased concentrations of ADM in the interstitium). Further, it is thought that adrecizumab prevents ADM from being degraded by proteases and prolongs half‐life of ADM …”

“…In animal models of systemic inflammation and septic shock, adrecizumab improved haemodynamics, renal function, systemic inflammation and reduced inducible nitric oxide synthase expression . Currently, adrecizumab is being evaluated in a phase II trial in human septic shock (http://clinicaltrials.gov identifier: NCT03085758).…”

“…The increase occurs within a few minutes and is not caused by induction of de-novo synthesis, because concentrations of MR-proADM are not increased (an inactive peptide fragment originating from the same precursor as ADM, which is synthesized in a 1:1 ratio). It is hypothesized that translocation of pre-existing ADM accounts for the observed increase in circulating ADM. 72 Briefly, circulating adrecizumab cannot leave the blood compartment due to its high molecular weight (160 kDa), whereas ADM (with a much lower molecular weight of 6 kDa) can freely cross the endothelial barrier between the interstitium and the circulation. 55 Binding of ADM by adrecizumab (present in the circulation in a large excess over ADM) prevents ADM from leaving the blood vessel, effectively 'trapping' ADM in the circulation.…”