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Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans
BACKGROUND: Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one‐third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420755/ https://www.ncbi.nlm.nih.gov/pubmed/34514376 http://dx.doi.org/10.1002/rco2.32 |
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author | Castillo, Alyssa Marie M. Vu, Trang T. Liva, Sophia G. Chen, Min Xie, Zhiliang Thomas, Justin Remaily, Bryan Guo, Yizhen Subrayan, Uma L. Costa, Travis Helms, Timothy H. Irby, Donald J. Kim, Kyeongmin Owen, Dwight H. Kulp, Samuel K. Mace, Thomas A. Phelps, Mitch A. Coss, Christopher C. |
author_facet | Castillo, Alyssa Marie M. Vu, Trang T. Liva, Sophia G. Chen, Min Xie, Zhiliang Thomas, Justin Remaily, Bryan Guo, Yizhen Subrayan, Uma L. Costa, Travis Helms, Timothy H. Irby, Donald J. Kim, Kyeongmin Owen, Dwight H. Kulp, Samuel K. Mace, Thomas A. Phelps, Mitch A. Coss, Christopher C. |
author_sort | Castillo, Alyssa Marie M. |
collection | PubMed |
description | BACKGROUND: Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one‐third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL(0)) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies. This suggests CL(0) may predict outcomes from ICI therapy, and cachectic signalling may link elevated CL(0) and poor response. Our aim was to determine if mouse models of cancer cachexia will be useful for studying these phenomena and their underlying mechanisms. METHODS: We evaluated pembrolizumab CL in the C26 and Lewis lung carcinoma mouse models of cancer cachexia. A single treatment of vehicle or pembrolizumab, at a dose of 2 or 10 mg/kg, was administered intravenously by tail vein injection. Pembrolizumab was quantified by an ELISA in serial plasma samples, and FcRn gene (Fcgrt) expression was assessed in liver using real‐time quantitative reverse transcription PCR. Non‐compartmental and mixed‐effects pharmacokinetics analyses were performed. RESULTS: We observed higher pembrolizumab CL(0) and decreased Fcgrt expression in whole liver tissue from tumour‐bearing vs. tumour‐free mice. In multivariate analysis, presence of tumour, total murine IgG, muscle weight and Fcgrt expression were significant covariates on CL, and total murine IgG was a significant covariate on V1 and Q. CONCLUSIONS: These data demonstrate increases in catabolic clearance of monoclonal antibodies observed in humans can be replicated in cachectic mice, in which Fcgrt expression is also reduced. Notably, FcRn activity is essential for proper antigen presentation and antitumour immunity, which may permit the study of cachexia's impact on FcRn‐mediated clearance and efficacy of ICI therapies. |
format | Online Article Text |
id | pubmed-8420755 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84207552021-09-10 Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans Castillo, Alyssa Marie M. Vu, Trang T. Liva, Sophia G. Chen, Min Xie, Zhiliang Thomas, Justin Remaily, Bryan Guo, Yizhen Subrayan, Uma L. Costa, Travis Helms, Timothy H. Irby, Donald J. Kim, Kyeongmin Owen, Dwight H. Kulp, Samuel K. Mace, Thomas A. Phelps, Mitch A. Coss, Christopher C. JCSM Rapid Commun Rapid Communication BACKGROUND: Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one‐third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL(0)) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies. This suggests CL(0) may predict outcomes from ICI therapy, and cachectic signalling may link elevated CL(0) and poor response. Our aim was to determine if mouse models of cancer cachexia will be useful for studying these phenomena and their underlying mechanisms. METHODS: We evaluated pembrolizumab CL in the C26 and Lewis lung carcinoma mouse models of cancer cachexia. A single treatment of vehicle or pembrolizumab, at a dose of 2 or 10 mg/kg, was administered intravenously by tail vein injection. Pembrolizumab was quantified by an ELISA in serial plasma samples, and FcRn gene (Fcgrt) expression was assessed in liver using real‐time quantitative reverse transcription PCR. Non‐compartmental and mixed‐effects pharmacokinetics analyses were performed. RESULTS: We observed higher pembrolizumab CL(0) and decreased Fcgrt expression in whole liver tissue from tumour‐bearing vs. tumour‐free mice. In multivariate analysis, presence of tumour, total murine IgG, muscle weight and Fcgrt expression were significant covariates on CL, and total murine IgG was a significant covariate on V1 and Q. CONCLUSIONS: These data demonstrate increases in catabolic clearance of monoclonal antibodies observed in humans can be replicated in cachectic mice, in which Fcgrt expression is also reduced. Notably, FcRn activity is essential for proper antigen presentation and antitumour immunity, which may permit the study of cachexia's impact on FcRn‐mediated clearance and efficacy of ICI therapies. John Wiley and Sons Inc. 2021-02-09 2021 /pmc/articles/PMC8420755/ /pubmed/34514376 http://dx.doi.org/10.1002/rco2.32 Text en © 2021 The Authors. JCSM Rapid Communications published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Rapid Communication Castillo, Alyssa Marie M. Vu, Trang T. Liva, Sophia G. Chen, Min Xie, Zhiliang Thomas, Justin Remaily, Bryan Guo, Yizhen Subrayan, Uma L. Costa, Travis Helms, Timothy H. Irby, Donald J. Kim, Kyeongmin Owen, Dwight H. Kulp, Samuel K. Mace, Thomas A. Phelps, Mitch A. Coss, Christopher C. Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans |
title | Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans |
title_full | Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans |
title_fullStr | Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans |
title_full_unstemmed | Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans |
title_short | Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans |
title_sort | murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans |
topic | Rapid Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420755/ https://www.ncbi.nlm.nih.gov/pubmed/34514376 http://dx.doi.org/10.1002/rco2.32 |
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