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Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension

Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right vent...

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Autores principales: Gouyou, Baptiste, Grün, Katja, Kerschenmeyer, Anne, Villa, Alessandra, Matasci, Mattia, Schrepper, Andrea, Pfeil, Alexander, Bäz, Laura, Jung, Christian, Schulze, P. Christian, Neri, Dario, Franz, Marcus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037792/
https://www.ncbi.nlm.nih.gov/pubmed/33801620
http://dx.doi.org/10.3390/ijms22073460
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author Gouyou, Baptiste
Grün, Katja
Kerschenmeyer, Anne
Villa, Alessandra
Matasci, Mattia
Schrepper, Andrea
Pfeil, Alexander
Bäz, Laura
Jung, Christian
Schulze, P. Christian
Neri, Dario
Franz, Marcus
author_facet Gouyou, Baptiste
Grün, Katja
Kerschenmeyer, Anne
Villa, Alessandra
Matasci, Mattia
Schrepper, Andrea
Pfeil, Alexander
Bäz, Laura
Jung, Christian
Schulze, P. Christian
Neri, Dario
Franz, Marcus
author_sort Gouyou, Baptiste
collection PubMed
description Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling.
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spelling pubmed-80377922021-04-12 Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension Gouyou, Baptiste Grün, Katja Kerschenmeyer, Anne Villa, Alessandra Matasci, Mattia Schrepper, Andrea Pfeil, Alexander Bäz, Laura Jung, Christian Schulze, P. Christian Neri, Dario Franz, Marcus Int J Mol Sci Article Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling. MDPI 2021-03-27 /pmc/articles/PMC8037792/ /pubmed/33801620 http://dx.doi.org/10.3390/ijms22073460 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Gouyou, Baptiste
Grün, Katja
Kerschenmeyer, Anne
Villa, Alessandra
Matasci, Mattia
Schrepper, Andrea
Pfeil, Alexander
Bäz, Laura
Jung, Christian
Schulze, P. Christian
Neri, Dario
Franz, Marcus
Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension
title Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension
title_full Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension
title_fullStr Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension
title_full_unstemmed Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension
title_short Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension
title_sort therapeutic evaluation of antibody-based targeted delivery of interleukin 9 in experimental pulmonary hypertension
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037792/
https://www.ncbi.nlm.nih.gov/pubmed/33801620
http://dx.doi.org/10.3390/ijms22073460
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