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Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model

INTRODUCTION: Adrenomedullin (ADM), a circulating vasodilatory peptide, plays an important role in the development of sepsis-associated hemodynamic and microcirculatory disorders. While administration of exogenous ADM had beneficial effects in several septic animal models, elevated ADM concentration...

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Autores principales: Struck, Joachim, Hein, Frauke, Karasch, Siegmund, Bergmann, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796695/
https://www.ncbi.nlm.nih.gov/pubmed/26266791
http://dx.doi.org/10.1186/2197-425X-1-3
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author Struck, Joachim
Hein, Frauke
Karasch, Siegmund
Bergmann, Andreas
author_facet Struck, Joachim
Hein, Frauke
Karasch, Siegmund
Bergmann, Andreas
author_sort Struck, Joachim
collection PubMed
description INTRODUCTION: Adrenomedullin (ADM), a circulating vasodilatory peptide, plays an important role in the development of sepsis-associated hemodynamic and microcirculatory disorders. While administration of exogenous ADM had beneficial effects in several septic animal models, elevated ADM concentrations are associated with a bad outcome. This prompted us to test the effect of various anti-ADM antibodies in a cecal ligation and puncture (CLP) mouse model. METHODS: To gain new potential compounds for the treatment or prevention of septic shock we followed an alternative strategy to influence the ADM system: High-affinity anti-ADM antibodies with different epitope specificities were developed and their antagonist activity in vitro and their ability to reduce mortality in a CLP mouse model were assessed. RESULTS: An anti-ADM antibody directed against the N-terminus substantially increased the survival of mice in a CLP model (HR = 0.077 (CI = 0.0189 to 0.315), p = 0.0004), whereas other antibodies with similar affinities but different epitope specificities were much less potent. The efficacious antibody, in contrast to an anti-C-terminal antibody, only partially inhibited ADM agonist activity in vitro. Healthy mice were not negatively affected by the N-terminal antibody. CONCLUSIONS: An anti-N-terminal ADM antibody, as opposed to antibodies with other epitope specificities, strongly reduces mortality in CLP mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2197-425X-1-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-47966952016-07-06 Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model Struck, Joachim Hein, Frauke Karasch, Siegmund Bergmann, Andreas Intensive Care Med Exp Research INTRODUCTION: Adrenomedullin (ADM), a circulating vasodilatory peptide, plays an important role in the development of sepsis-associated hemodynamic and microcirculatory disorders. While administration of exogenous ADM had beneficial effects in several septic animal models, elevated ADM concentrations are associated with a bad outcome. This prompted us to test the effect of various anti-ADM antibodies in a cecal ligation and puncture (CLP) mouse model. METHODS: To gain new potential compounds for the treatment or prevention of septic shock we followed an alternative strategy to influence the ADM system: High-affinity anti-ADM antibodies with different epitope specificities were developed and their antagonist activity in vitro and their ability to reduce mortality in a CLP mouse model were assessed. RESULTS: An anti-ADM antibody directed against the N-terminus substantially increased the survival of mice in a CLP model (HR = 0.077 (CI = 0.0189 to 0.315), p = 0.0004), whereas other antibodies with similar affinities but different epitope specificities were much less potent. The efficacious antibody, in contrast to an anti-C-terminal antibody, only partially inhibited ADM agonist activity in vitro. Healthy mice were not negatively affected by the N-terminal antibody. CONCLUSIONS: An anti-N-terminal ADM antibody, as opposed to antibodies with other epitope specificities, strongly reduces mortality in CLP mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2197-425X-1-3) contains supplementary material, which is available to authorized users. Springer International Publishing 2013-10-29 /pmc/articles/PMC4796695/ /pubmed/26266791 http://dx.doi.org/10.1186/2197-425X-1-3 Text en © Struck et al.; licensee Springer. 2013 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Struck, Joachim
Hein, Frauke
Karasch, Siegmund
Bergmann, Andreas
Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model
title Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model
title_full Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model
title_fullStr Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model
title_full_unstemmed Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model
title_short Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model
title_sort epitope specificity of anti-adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796695/
https://www.ncbi.nlm.nih.gov/pubmed/26266791
http://dx.doi.org/10.1186/2197-425X-1-3
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