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Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative

Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepa...

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Autores principales: Petersen, Maj, Gandhi, Prafull S., Buchardt, Jens, Alanentalo, Tomas, Fels, Johannes Josef, Johansen, Nils Langeland, Helding-Kvist, Peter, Vad, Knud, Thygesen, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072805/
https://www.ncbi.nlm.nih.gov/pubmed/32053994
http://dx.doi.org/10.3390/ijms21041181
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author Petersen, Maj
Gandhi, Prafull S.
Buchardt, Jens
Alanentalo, Tomas
Fels, Johannes Josef
Johansen, Nils Langeland
Helding-Kvist, Peter
Vad, Knud
Thygesen, Peter
author_facet Petersen, Maj
Gandhi, Prafull S.
Buchardt, Jens
Alanentalo, Tomas
Fels, Johannes Josef
Johansen, Nils Langeland
Helding-Kvist, Peter
Vad, Knud
Thygesen, Peter
author_sort Petersen, Maj
collection PubMed
description Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepatocellular models and using isothermal titration calorimetry to characterize receptor binding of somapacitan in the presence or absence of human serum albumin (HSA). With non-invasive fluorescence imaging we quantitatively visualize and compare the temporal distribution and examine the tissue-specific growth hormone receptor (GHR) activation at distribution sites. We found that signaling kinetics were slightly more rapid and intense for GH compared with somapacitan. Receptor binding isotherms were characterized by a high and a low affinity interaction site with or without HSA. Using in vivo optical imaging we found prolonged systemically biodistribution of somapacitan compared with GH, which correlated with plasma pharmacokinetics. Ex vivo mouse organ analysis revealed that the temporal fluorescent intensity in livers dosed with somapacitan was significantly increased compared with GH-dosed livers and correlated with the degree of downstream GHR activation. Finally, we show that fluorescent-labeled analogs distributed to the hypertrophic zone in the epiphysis of proximal tibia of hypophysectomized rats and that somapacitan and GH activate the GHR signaling in epiphyseal tissues.
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spelling pubmed-70728052020-03-19 Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative Petersen, Maj Gandhi, Prafull S. Buchardt, Jens Alanentalo, Tomas Fels, Johannes Josef Johansen, Nils Langeland Helding-Kvist, Peter Vad, Knud Thygesen, Peter Int J Mol Sci Article Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepatocellular models and using isothermal titration calorimetry to characterize receptor binding of somapacitan in the presence or absence of human serum albumin (HSA). With non-invasive fluorescence imaging we quantitatively visualize and compare the temporal distribution and examine the tissue-specific growth hormone receptor (GHR) activation at distribution sites. We found that signaling kinetics were slightly more rapid and intense for GH compared with somapacitan. Receptor binding isotherms were characterized by a high and a low affinity interaction site with or without HSA. Using in vivo optical imaging we found prolonged systemically biodistribution of somapacitan compared with GH, which correlated with plasma pharmacokinetics. Ex vivo mouse organ analysis revealed that the temporal fluorescent intensity in livers dosed with somapacitan was significantly increased compared with GH-dosed livers and correlated with the degree of downstream GHR activation. Finally, we show that fluorescent-labeled analogs distributed to the hypertrophic zone in the epiphysis of proximal tibia of hypophysectomized rats and that somapacitan and GH activate the GHR signaling in epiphyseal tissues. MDPI 2020-02-11 /pmc/articles/PMC7072805/ /pubmed/32053994 http://dx.doi.org/10.3390/ijms21041181 Text en © 2020 by the authors. 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/).
spellingShingle Article
Petersen, Maj
Gandhi, Prafull S.
Buchardt, Jens
Alanentalo, Tomas
Fels, Johannes Josef
Johansen, Nils Langeland
Helding-Kvist, Peter
Vad, Knud
Thygesen, Peter
Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative
title Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative
title_full Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative
title_fullStr Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative
title_full_unstemmed Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative
title_short Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative
title_sort tissue distribution and receptor activation by somapacitan, a long acting growth hormone derivative
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072805/
https://www.ncbi.nlm.nih.gov/pubmed/32053994
http://dx.doi.org/10.3390/ijms21041181
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