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Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities

Osteopontin is a secreted glycophosphoprotein that is highly implicated in many physiological and pathological processes such as biomineralization, cell-mediated immunity, inflammation, fibrosis, cell survival, tumorigenesis and metastasis. Antibodies against osteopontin have been actively pursued a...

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Autores principales: Farrokhi, Vahid, Chabot, Jeffrey R., Neubert, Hendrik, Yang, Zhiyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958109/
https://www.ncbi.nlm.nih.gov/pubmed/29773891
http://dx.doi.org/10.1038/s41598-018-26187-w
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author Farrokhi, Vahid
Chabot, Jeffrey R.
Neubert, Hendrik
Yang, Zhiyong
author_facet Farrokhi, Vahid
Chabot, Jeffrey R.
Neubert, Hendrik
Yang, Zhiyong
author_sort Farrokhi, Vahid
collection PubMed
description Osteopontin is a secreted glycophosphoprotein that is highly implicated in many physiological and pathological processes such as biomineralization, cell-mediated immunity, inflammation, fibrosis, cell survival, tumorigenesis and metastasis. Antibodies against osteopontin have been actively pursued as potential therapeutics for various diseases by pharmaceutical companies and academic laboratories. Many studies have demonstrated the efficacy of osteopontin inhibition in a variety of preclinical models of diseases such as rheumatoid arthritis, cancer, nonalcoholic steatohepatitis, but clinical utility has not yet been demonstrated. To evaluate the feasibility of osteopontin neutralization with antibodies in a clinical setting, we measured its physiological turnover rate in humans, a sensitive parameter required for mechanistic pharmacokinetic and pharmacodynamic (PK/PD) modeling of biotherapeutics. Results from a stable isotope-labelled amino acid pulse-chase study in healthy human subjects followed by mass spectrometry showed that osteopontin undergoes very rapid turnover. PK/PD modeling and simulation of different theoretical scenarios reveal that achieving sufficient target coverage using antibodies can be very challenging mostly due to osteopontin’s fast turnover, as well as its relatively high plasma concentrations in human. Therapeutic antibodies against osteopontin would need to be engineered to have much extended PK than conventional antibodies, and be administered at high doses and with short dosing intervals.
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spelling pubmed-59581092018-05-24 Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities Farrokhi, Vahid Chabot, Jeffrey R. Neubert, Hendrik Yang, Zhiyong Sci Rep Article Osteopontin is a secreted glycophosphoprotein that is highly implicated in many physiological and pathological processes such as biomineralization, cell-mediated immunity, inflammation, fibrosis, cell survival, tumorigenesis and metastasis. Antibodies against osteopontin have been actively pursued as potential therapeutics for various diseases by pharmaceutical companies and academic laboratories. Many studies have demonstrated the efficacy of osteopontin inhibition in a variety of preclinical models of diseases such as rheumatoid arthritis, cancer, nonalcoholic steatohepatitis, but clinical utility has not yet been demonstrated. To evaluate the feasibility of osteopontin neutralization with antibodies in a clinical setting, we measured its physiological turnover rate in humans, a sensitive parameter required for mechanistic pharmacokinetic and pharmacodynamic (PK/PD) modeling of biotherapeutics. Results from a stable isotope-labelled amino acid pulse-chase study in healthy human subjects followed by mass spectrometry showed that osteopontin undergoes very rapid turnover. PK/PD modeling and simulation of different theoretical scenarios reveal that achieving sufficient target coverage using antibodies can be very challenging mostly due to osteopontin’s fast turnover, as well as its relatively high plasma concentrations in human. Therapeutic antibodies against osteopontin would need to be engineered to have much extended PK than conventional antibodies, and be administered at high doses and with short dosing intervals. Nature Publishing Group UK 2018-05-17 /pmc/articles/PMC5958109/ /pubmed/29773891 http://dx.doi.org/10.1038/s41598-018-26187-w Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Farrokhi, Vahid
Chabot, Jeffrey R.
Neubert, Hendrik
Yang, Zhiyong
Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities
title Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities
title_full Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities
title_fullStr Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities
title_full_unstemmed Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities
title_short Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities
title_sort assessing the feasibility of neutralizing osteopontin with various therapeutic antibody modalities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958109/
https://www.ncbi.nlm.nih.gov/pubmed/29773891
http://dx.doi.org/10.1038/s41598-018-26187-w
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