Dataset Information

Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6 Antibody

ABSTRACT: Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6 Antibody This model is comprised of four models: [BIOMD0000000534] Healthy Volunteer model [BIOMD0000000535] Crohn's Disease - IL-6 Antibody [BIOMD0000000536] Crohn's Disease - sgp130FC [BIOMD0000000537] Crohn's Disease - IL-6Ra Antibody Possible avenues for Interleukin-6 (IL-6) inhibition in treating Crohn's disease are compared here. Each model refers to separate ligands. The system simulates differential activity of the ligands on the signalling of IL-6. This affects Signal Transducer and Activator of Transcription 3 (STAT3) activity on the production of biomarker C-Reactive Protein (CRP) expression. Figures referring to this Crohn's Disease model are 4a, 4b, 4c and 5a. This model is described in the article: A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development. Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C. CPT Pharmacometrics Syst Pharmacol 2014; 3: e89 Abstract: In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6R? complex in addition to IL-6 or IL-6R?. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014. This model is hosted on BioModels Database and identified by: BIOMD0000000535. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

DISEASE(S): Crohn's Disease

SUBMITTER: Vincent Knight-Schrijver

PROVIDER: BIOMD0000000535 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development.

Dwivedi G G Fitz L L Hegen M M Martin S W SW Harrold J J Heatherington A A Li C C

CPT: pharmacometrics & systems pharmacology 20140108

In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to devel ...[more]

PMID: 24402116

Similar Datasets

Project description:Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody This model is comprised of four models: [BIOMD0000000534] Healthy Volunteer model [BIOMD0000000535] Crohn's Disease - IL-6 Antibody [BIOMD0000000536] Crohn's Disease - sgp130FC [BIOMD0000000537] Crohn's Disease - IL-6Ra Antibody Possible avenues for Interleukin-6 (IL-6) inhibition in treating Crohn's disease are compared here. Each model refers to separate ligands. The system simulates differential activity of the ligands on the signalling of IL-6. This affects Signal Transducer and Activator of Transcription 3 (STAT3) activity on the production of biomarker C-Reactive Protein (CRP) expression. Figures referring to this Crohn's Disease model are 3a, 4d, 4e, 4f and 5b. This model is described in the article: A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development. Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C. CPT Pharmacometrics Syst Pharmacol 2014; 3: e89 Abstract: In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6R? complex in addition to IL-6 or IL-6R?. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014. This model is hosted on BioModels Database and identified by: BIOMD0000000537. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Dwivedi2014 - Healthy Volunteer IL6 Model This model is comprised of four models: [BIOMD0000000534] Healthy Volunteer model [BIOMD0000000535] Crohn's Disease - IL-6 Antibody [BIOMD0000000536] Crohn's Disease - sgp130FC [BIOMD0000000537] Crohn's Disease - IL-6Ra Antibody Possible avenues for Interleukin-6 (IL-6) inhibition in treating Crohn's disease are compared here. Each model refers to separate ligands. The system simulates differential activity of the ligands on the signalling of IL-6. This affects Signal Transducer and Activator of Transcription 3 (STAT3) activity on the production of biomarker C-Reactive Protein (CRP) expression. Figures referring to this Healthy Volunteer model are 2c and 2d. This model is described in the article: A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development. Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C. CPT Pharmacometrics Syst Pharmacol 2014; 3: e89 Abstract: In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6R? complex in addition to IL-6 or IL-6R?. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014. This model is hosted on BioModels Database and identified by: BIOMD0000000534. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Dwivedi2014 - Crohns IL6 Disease model - sgp130 activity This model is comprised of four models: [BIOMD0000000534] Healthy Volunteer model [BIOMD0000000535] Crohn's Disease - IL-6 Antibody [BIOMD0000000536] Crohn's Disease - sgp130FC [BIOMD0000000537] Crohn's Disease - IL-6Ra Antibody Possible avenues for Interleukin-6 (IL-6) inhibition in treating Crohn's disease are compared here. Each model refers to separate ligands. The system simulates differential activity of the ligands on the signalling of IL-6. This affects Signal Transducer and Activator of Transcription 3 (STAT3) activity on the production of biomarker C-Reactive Protein (CRP) expression. The figure referring to this Crohn's Disease model is 6b. This model is described in the article: A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development. Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C. CPT Pharmacometrics Syst Pharmacol 2014; 3: e89 Abstract: In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6R? complex in addition to IL-6 or IL-6R?. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014. This model is hosted on BioModels Database and identified by: BIOMD0000000536. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:This a model from the article: A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment Fereshteh Nazari, Alexander T. Pearson, Jacques Eduardo Nor, Trachette L. Jackson. PloS Computational Biology, 2018 Jan. Abstract: Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth. Author Summary: A small population of cancer stem cells that share many of the biological characteristics of normal adult stem cells are believed to initiate and sustain tumor growth for a wide variety of malignancies. Growth and survival of these cancer stem cells is highly influenced by tumor micro-environmental factors and molecular signaling initiated by cytokines and growth factors. This work focuses on quantifying the influence of IL-6, a pleiotropic cytokine secreted by a variety of cell types, on cancer stem cell self-renewal and survival. We present a mathematical model for IL-6 mediated, cancer stem cell driven tumor growth that operates at the following levels: (1) the molecular level—capturing cell surface dynamics of receptor-ligand binding and receptor activation that lead to intra-cellular signal transduction cascades; and (2) the cellular level—describing tumor growth, cellular composition, and response to treatments targeted against IL-6. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.