Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody

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Short description
Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R 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 3a, 4d, 4e, 4f and 5b.

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
Vincent Knight-Schrijver

Metadata information

is
BioModels Database MODEL1408050002
BioModels Database BIOMD0000000537
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
  • Model originally submitted by : Vincent Knight-Schrijver
  • Submitted: Aug 5, 2014 1:46:06 PM
  • Last Modified: Jan 13, 2017 4:03:17 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Jan 13, 2017 4:03:17 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Current version of Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody
  • Version: 1 public model Download this version
    • Submitted on: Aug 5, 2014 1:46:06 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Original import of Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody
Curator's comment:
(added: 06 Aug 2014, 16:42:23, updated: 06 Aug 2014, 16:42:23)
Figure 3a: Reduction of CRP from baseline with administration of Tocilizumab, an anti IL6-R antibody. Doses of 560 mg every 2 weeks and 4 weeks were simulated. Simulated as two time courses, 2 weeks and 4 weeks. The antibody Kd was matched to Tocilizumab for this case (1 nmol/l). Figure 4d: Concentration of serum IL6, gut IL6 serum CRP and Gut pSTAT3 with a monthly (672 h) 300 mg dose regimen of IL6-R antibody. Simulated as a Time Course for 2016 h. Figure 4e: Suppression of CRP by IL6-R antibody after 12 weeks of monthly (672 h) doses. Three separate Kd values were assessed: 2.5, 25 and 250 pmol/l. Simulated with a two-paramater scan for Dose and Kd, Plotted using LibreCalc. Figure 4f: IL6-R antibody concentration in serum for 200 and 500 mg doses administered monthly (672 hours). Simulated as a parameter scan for Dose between 200 and 500 with 1 interval. Figure 5b: 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 with a two-paramater scan for Dose and Kd, Plotted using LibreCalc