Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6 Antibody

View the 2014-09 Model of the Month entry for this model
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Short description
Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6 Antibody
This model is comprised of four models:
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:

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.

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.

Format
SBML (L2V4)
Related Publication
  • 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 & systems pharmacology , 0/ 2014 , Volume 3 , pages: e89
  • The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.
  • 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-6Rα, or the IL-6/sIL-6Rα complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6Rα complex in addition to IL-6 or IL-6Rα. 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.
Contributors
administrator, Vincent Knight-Schrijver

Metadata information

is
BioModels Database MODEL1408050001
BioModels Database BIOMD0000000535
isDescribedBy
PubMed 24402116
hasTaxon
Taxonomy Homo sapiens
isVersionOf
hasPart
Gene Ontology JAK-STAT cascade
isPartOf
Reactome REACT_27307.1
hasVersion
Human Disease Ontology Crohn's disease
Curation status
Curated
Name Description Size Actions

Model files

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BIOMD0000000535-biopax2.owl Auto-generated BioPAX (Level 2) 116.94 KB Preview | Download
BIOMD0000000535.svg Auto-generated Reaction graph (SVG) 248.47 KB Preview | Download
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Dwivedi2014_IL6_curation_log.txt.zip Curation log.txt file summarising all changes made to original model. Includes details of figure reproduction. 2.27 KB Preview | Download
BIOMD0000000535.sci Auto-generated Scilab file 67.00 bytes Preview | Download
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BIOMD0000000535_urn.xml Auto-generated SBML file with URNs 220.60 KB Preview | Download
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  • Model originally submitted by : administrator
  • Submitted: Aug 5, 2014 1:44:00 PM
  • Last Modified: Dec 21, 2018 5:28:48 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 5:28:48 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: Dwivedi2014_IL6_curation_log.txt.zip
  • Version: 2 public model Download this version
    • Submitted on: Jan 13, 2017 4:02:44 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Current version of Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6 Antibody
  • Version: 1 public model Download this version
    • Submitted on: Aug 5, 2014 1:44:00 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Original import of Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6 Antibody
Curator's comment:
(added: 06 Aug 2014, 12:41:12, updated: 06 Aug 2014, 12:41:12)
Figure 4a: Figure 4a: Concentration of serum IL6, gut IL6 serum CRP and Gut pSTAT3 with a monthly (672 h) 300 mg dose regimen of IL6 antibody. Simulated with a Time Course for 2016 h (12 weeks). Figure 4b: Suppression of CRP by IL6 antibody after 12 weeks of monthly (672 h) doses. Three separate Kd values were assessed: 2.5, 25 and 250 pmol/l. Simulated using a two-parameter scan for dose and Kd and plotted separately on libreCalc. Figure 4c: IL6 antibody concentration in serum for 200 and 500 mg doses administered monthly (672 hours). Simulated using a parameter scan for dose between 200 and 500 mg with 1 logarithmic interval. Figure 5a: Suppression of CRP after 12 weeks of varied monthly (672 hours) doses. This simulation includes binding of the antibody to the ligand-receptor complex. Three separate Kd values were assessed: 2.5, 25 and 250 pmol/l. Simulated using a two-parameter scan for dose and Kd and plotted separately on libreCalc.