Schropp2019 - Target-Mediated Drug Disposition Model for Bispecific Antibodies
View the 2019-10 Model of the Month entry for this model
Model Identifier
BIOMD0000000788
Short description
This model presents a general target-mediated drug disposition (TMDD) model for bispecific antibodies (BsAbs), which bind to two different targets on different cell membranes. The model includes four different binding events for BsAbs, turnover of the targets, and internalization of the complexes. In addition, a quasi-equilibrium (QE) approximation with decreased number of binding parameters is also present.
Format
SBML
(L2V4)
Related Publication
-
Target-Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy.
- Schropp J, Khot A, Shah DK, Koch G
- CPT: pharmacometrics & systems pharmacology , 3/ 2019 , Volume 8 , Issue 3 , pages: 177-187 , PubMed ID: 30480383
- Department of Mathematics and Statistics, University of Konstanz, Konstanz, Germany.
- Bispecific antibodies (BsAbs) bind to two different targets, and create two binary and one ternary complex (TC). These molecules have shown promise as immuno-oncology drugs, and the TC is considered the pharmacologically active species that drives their pharmacodynamic effect. Here, we have presented a general target-mediated drug disposition (TMDD) model for these BsAbs, which bind to two different targets on different cell membranes. The model includes four different binding events for BsAbs, turnover of the targets, and internalization of the complexes. In addition, a quasi-equilibrium (QE) approximation with decreased number of binding parameters and, if necessary, reduced internalization parameters is presented. The model is further used to investigate the kinetics of BsAb and TC concentrations. Our analysis shows that larger doses of BsAbs may delay the build-up of the TC. Consequently, a method to compute the optimal dosing strategy of BsAbs, which will immediately create and maintain maximal possible TC concentration, is presented.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Metadata information
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hasTaxon (1 statement)
hasProperty (1 statement)
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isDescribedBy (1 statement)
hasTaxon (1 statement)
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Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
Name | Description | Size | Actions |
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Model files |
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Schropp2019.xml | SBML L2V4 Schropp2019 - Target-Mediated Drug Disposition Model for Bispecific Antibodies | 87.54 KB | Preview | Download |
Additional files |
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Schropp2019.cps | COPASI file of Schropp2019 - Target-Mediated Drug Disposition Model for Bispecific Antibodies | 120.38 KB | Preview | Download |
Schropp2019.sedml | SED-ML file of Schropp2019 - Target-Mediated Drug Disposition Model for Bispecific Antibodies | 1.72 KB | Preview | Download |
- Model originally submitted by : Johannes Meyer
- Submitted: Aug 12, 2019 10:32:33 AM
- Last Modified: Aug 12, 2019 10:32:33 AM
Revisions
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
Species | Initial Concentration/Amount |
---|---|
C free Bispecific Monoclonal Antibody |
50.0 nmol |
R B Receptor |
100.0 nmol |
RC B Receptor ; Bispecific Monoclonal Antibody ; macromolecular complex |
0.0 nmol |
AD Bispecific Antibody ; Bispecific Monoclonal Antibody ; Subcutaneous Route of Administration |
0.0 nmol |
RC A Receptor ; Bispecific Monoclonal Antibody ; macromolecular complex |
0.0 nmol |
AP Bispecific Antibody ; Bispecific Monoclonal Antibody ; peripheral blood |
0.0 nmol |
Reactions
Reactions | Rate | Parameters |
---|---|---|
C_free + R_B => RC_B | Central*k_on_2*C_free*R_B | k_on_2 = 1.0 ml/(mol*s) |
RC_A + R_B => RC_AB | Central*k_on_3*RC_A*R_B | k_on_3 = 1.0 ml/(mol*s) |
=> RC_B + R_B; RC_AB | Central*k_off_3*RC_AB | k_off_3 = 0.01 1/ms |
AD => | Peripheral*k_a*AD | k_a = 0.2 1/ms |
=> C_free + R_B; RC_B | Central*k_off_2*RC_B | k_off_2 = 0.01 1/ms |
=> RC_A + R_A; RC_AB | Central*k_off_4*RC_AB | k_off_4 = 0.01 1/ms |
=> C_free + R_A; RC_A | Central*k_off_1*RC_A | k_off_1 = 0.01 1/ms |
=> AP; C_free | k_12*C_free*V | k_12 = 0.1 1/ms; V = 3.0 l |
C_free + R_A => RC_A | Central*k_on_1*C_free*R_A | k_on_1 = 10.0 ml/(mol*s) |
Curator's comment:
(added: 12 Aug 2019, 10:32:22, updated: 12 Aug 2019, 10:32:22)
(added: 12 Aug 2019, 10:32:22, updated: 12 Aug 2019, 10:32:22)
Reproduced plot of Figure 3B in the original publication.
Model simulated and plot produced using COPASI 4.24 (Build 197).