Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody

View the 2014-09 Model of the Month entry for this model
  public model
Model Identifier
BIOMD0000000537
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 , PubMed ID: 24402116
  • 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, administrator

Metadata information

is
BioModels Database MODEL1408050002
BioModels Database BIOMD0000000537
isDescribedBy
PubMed 24402116
hasTaxon
Taxonomy Homo sapiens
isVersionOf
hasPart
Gene Ontology JAK-STAT cascade
isPartOf
hasVersion
Human Disease Ontology Crohn's disease

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000537_url.xml SBML L2V4 representation of Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody 248.69 KB Preview | Download

Additional files

BIOMD0000000537.sci Auto-generated Scilab file 67.00 bytes Preview | Download
BIOMD0000000537.vcml Auto-generated VCML file 897.00 bytes Preview | Download
Dwivedi2014_IL6R_curation_log.txt.zip Curation log.txt file summarising all changes made to original model. Includes details of figure reproduction. 2.43 KB Preview | Download
BIOMD0000000537.m Auto-generated Octave file 64.30 KB Preview | Download
BIOMD0000000537-biopax3.owl Auto-generated BioPAX (Level 3) 206.39 KB Preview | Download
BIOMD0000000537.svg Auto-generated Reaction graph (SVG) 255.34 KB Preview | Download
BIOMD0000000537_urn.xml Auto-generated SBML file with URNs 248.06 KB Preview | Download
BIOMD0000000537.xpp Auto-generated XPP file 49.84 KB Preview | Download
BIOMD0000000537.pdf Auto-generated PDF file 808.89 KB Preview | Download
BIOMD0000000537-biopax2.owl Auto-generated BioPAX (Level 2) 120.83 KB Preview | Download
BIOMD0000000537.png Auto-generated Reaction graph (PNG) 887.65 KB Preview | Download

  • Model originally submitted by : Vincent Knight-Schrijver
  • Submitted: 05-Aug-2014 13:46:06
  • Last Modified: 21-Dec-2018 17:29:26
Revisions
  • Version: 3 public model Download this version
    • Submitted on: 21-Dec-2018 17:29:26
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: Dwivedi2014_IL6R_curation_log.txt.zip
  • Version: 2 public model Download this version
    • Submitted on: 13-Jan-2017 16:03:17
    • 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: 05-Aug-2014 13:46:06
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Original import of Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
mw7d86cc23 a1af 44c3 bdb9 71e9b1bb2a83

Interleukin-6 receptor subunit alpha ; Interleukin-6
1.60036523605187E-5 nmol
mw0eb6c959 d408 45a0 a450 928b8c5876bb

Interleukin-6 receptor subunit alpha ; Interleukin-6 ; interleukin-6 receptor subunit beta ; SBO:0000286; active
0.765416493681823 nmol
mw42054cd7 17af 46da 970c 7f99151906ad

signal transducer and activator of transcription 3
0.777537339578333 nmol
mw39c2e431 fdc3 4964 be29 6ca856620b1b

phosphorylation ; signal transducer and activator of transcription 3
9.22246266042168 nmol
mwd5313618 89eb 4c8c bc82 66f10f966349

C-reactive protein
158.325846781611 nmol
mw2e464cf3 a09c 4b7c 9f3c 06720016a48e

soluble in ; Interleukin-6 receptor subunit alpha
6.08704712819469 nmol
mw36ea78c1 ed71 4def 96d3 857a442d7195

C-reactive protein
409.775322370541 nmol
mw147d30ec 478e 4090 b496 128a131d29eb

interleukin-6 receptor subunit beta ; soluble in
5.5896988923534 nmol
mwab41493c 6349 45f1 a226 3030cfed0e06

Interleukin-6 ; Interleukin-6 receptor subunit alpha ; interleukin-6 receptor subunit beta ; soluble in
0.116343661809953 nmol
mwf405687b 7401 44ec a0d6 4a2b35c13e8a

Interleukin-6 receptor subunit alpha ; Immunoglobulin ; soluble in
8.616193096436E-26 nmol
mw30ae63db 6cd3 4b6f 93ad 3350cd360bcc

Interleukin-6 receptor subunit alpha ; soluble in
4.25350679194445 nmol
mw8c9107e6 f51d 442d b2dc 2bfdbb8482ca

interleukin-6 receptor subunit beta
0.374962692933961 nmol
Reactions
Reactions Rate Parameters
mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*(kgp130On*mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83*mw80848184_e2dd_47ce_86d7_7a21479342bd-kgp130Off*mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e

mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*(kgp130On*mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83*mw80848184_e2dd_47ce_86d7_7a21479342bd-kgp130Off*mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e
kgp130Off = 1.026; kgp130On = 20.52
mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*kRAct*mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e

mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*kRAct*mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e
kRAct = 155.0
mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a*mw0eb6c959_d408_45a0_a450_928b8c5876bb/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e

mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a*mw0eb6c959_d408_45a0_a450_928b8c5876bb/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e
mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a = 0.01
mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*mw9442cd0e_4d7c_4ba6_a695_f84919bdf569*mw0eb6c959_d408_45a0_a450_928b8c5876bb*mw42054cd7_17af_46da_970c_7f99151906ad/(mwe8fc1900_f07d_468b_b5c8_15400a583c3d+mw42054cd7_17af_46da_970c_7f99151906ad)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e

mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*mw9442cd0e_4d7c_4ba6_a695_f84919bdf569*mw0eb6c959_d408_45a0_a450_928b8c5876bb*mw42054cd7_17af_46da_970c_7f99151906ad/(mwe8fc1900_f07d_468b_b5c8_15400a583c3d+mw42054cd7_17af_46da_970c_7f99151906ad)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e
mwe8fc1900_f07d_468b_b5c8_15400a583c3d = 219.0; mw9442cd0e_4d7c_4ba6_a695_f84919bdf569 = 145.0
mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*mwd36b0261_2480_4cab_9222_2cf8fb0e65dc*mw39c2e431_fdc3_4964_be29_6ca856620b1b/(mwfd291862_195f_4979_94b5_b4e5ae1b7d52+mw39c2e431_fdc3_4964_be29_6ca856620b1b)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e

mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*mwd36b0261_2480_4cab_9222_2cf8fb0e65dc*mw39c2e431_fdc3_4964_be29_6ca856620b1b/(mwfd291862_195f_4979_94b5_b4e5ae1b7d52+mw39c2e431_fdc3_4964_be29_6ca856620b1b)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e
mwfd291862_195f_4979_94b5_b4e5ae1b7d52 = 5.34; mwd36b0261_2480_4cab_9222_2cf8fb0e65dc = 0.62
mw08950572_81b0_4570_b2e4_b9c3462c1425 = 10.0; mw92d854a7_8aaf_458e_b5e2_20a63ce9b654 = 330.0
mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*(mwa09d6284_843e_404e_abbb_052fbb535197*mw3667a5e1_02c9_44a0_acb4_b0431faa822d*mw2e464cf3_a09c_4b7c_9f3c_06720016a48e-mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead*mwf405687b_7401_44ec_a0d6_4a2b35c13e8a)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e

mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*(mwa09d6284_843e_404e_abbb_052fbb535197*mw3667a5e1_02c9_44a0_acb4_b0431faa822d*mw2e464cf3_a09c_4b7c_9f3c_06720016a48e-mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead*mwf405687b_7401_44ec_a0d6_4a2b35c13e8a)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e
mwa09d6284_843e_404e_abbb_052fbb535197 = 1000.0; mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead = 2.5
mwc67e1333_079a_4bea_9b4f_0a1b15ddd7bb*mw114aa90f_5f5b_4fe8_9406_361c8489b6a1-mwce10678d_8197_408c_ad47_1daec8104cd8*mw36ea78c1_ed71_4def_96d3_857a442d7195

mwc67e1333_079a_4bea_9b4f_0a1b15ddd7bb*mw114aa90f_5f5b_4fe8_9406_361c8489b6a1-mwce10678d_8197_408c_ad47_1daec8104cd8*mw36ea78c1_ed71_4def_96d3_857a442d7195
mwce10678d_8197_408c_ad47_1daec8104cd8 = 0.8473; mwc67e1333_079a_4bea_9b4f_0a1b15ddd7bb = 1.2125
mwc67e1333_079a_4bea_9b4f_0a1b15ddd7bb*mwbbbce920_e8dd_4320_9386_fc94bfb2fc99-mwce10678d_8197_408c_ad47_1daec8104cd8*mw147d30ec_478e_4090_b496_128a131d29eb

mwc67e1333_079a_4bea_9b4f_0a1b15ddd7bb*mwbbbce920_e8dd_4320_9386_fc94bfb2fc99-mwce10678d_8197_408c_ad47_1daec8104cd8*mw147d30ec_478e_4090_b496_128a131d29eb
mwce10678d_8197_408c_ad47_1daec8104cd8 = 0.8473; mwc67e1333_079a_4bea_9b4f_0a1b15ddd7bb = 1.2125
mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*(kgp130On*mw4638f126_8cb8_4021_ab41_6ae195743ba0*mw147d30ec_478e_4090_b496_128a131d29eb-kgp130Off*mwab41493c_6349_45f1_a226_3030cfed0e06)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e

mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*(kgp130On*mw4638f126_8cb8_4021_ab41_6ae195743ba0*mw147d30ec_478e_4090_b496_128a131d29eb-kgp130Off*mwab41493c_6349_45f1_a226_3030cfed0e06)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e
kgp130Off = 1.026; kgp130On = 20.52
mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mwf405687b_7401_44ec_a0d6_4a2b35c13e8a/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e

mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e*mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mwf405687b_7401_44ec_a0d6_4a2b35c13e8a/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e
mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 = 0.0018
mw53ffe9e6_beef_45c4_90a5_a79197ed506e*mwc4c58db7_5535_4590_aaa5_bbc8ed53cdab/mw53ffe9e6_beef_45c4_90a5_a79197ed506e

mw53ffe9e6_beef_45c4_90a5_a79197ed506e*mwc4c58db7_5535_4590_aaa5_bbc8ed53cdab/mw53ffe9e6_beef_45c4_90a5_a79197ed506e
mwc4c58db7_5535_4590_aaa5_bbc8ed53cdab = 0.1
mwe9501423_9fb4_494b_b5b6_288f3fcb17b5*(kgp130On*mw7becb5fe_8da8_4285_a821_0d77ad811b62*mw8c9107e6_f51d_442d_b2dc_2bfdbb8482ca-kgp130Off*mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5

mwe9501423_9fb4_494b_b5b6_288f3fcb17b5*(kgp130On*mw7becb5fe_8da8_4285_a821_0d77ad811b62*mw8c9107e6_f51d_442d_b2dc_2bfdbb8482ca-kgp130Off*mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5
kgp130Off = 1.026; kgp130On = 20.52
mwe9501423_9fb4_494b_b5b6_288f3fcb17b5*kRsynth/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5

mwe9501423_9fb4_494b_b5b6_288f3fcb17b5*kRsynth/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5
kRsynth = 0.0685
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