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Quantitative Pharmacology Methods for Bispecific T Cell Engagers
Mahdiar Sadeghi1,2, Irina Kareva2,3, Gleb Pogudin4
1Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA.
Abstract:
T Cell Engager (TCE)s are an exciting therapeutic modality in immuno-oncology that acts to bypass antigen presentation and forms a direct link between cancer and immune cells in the Tumor Microenvironment (TME). TCEs are efficacious only when the drug is bound to both immune and cancer cell targets. Therefore, approaches that maximize the formation of the drug-target trimer in the TME are expected to increase the drug's efficacy. In this study, we quantitatively investigate how the concentration of ternary complex and its biodistribution depend on both the targets' specific properties and the design characteristics of the TCE, and specifically on the binding kinetics of the drug to its targets. A simplified mathematical model of drug-target interactions is considered here, with insights from the "three-body" problem applied to the model. Parameter identifiability analysis performed on the model demonstrates that steady state data, which is often available at the early pre-clinical stages, is sufficient to estimate the binding affinity of the TCE molecule to both targets. We used the model to analyze several existing antibodies, both clinically approved and under development, to explore their common kinetic features. The manuscript concludes with an assessment of a full quantitative pharmacology model that accounts for drug disposition into the peripheral compartment.
Insights
T Cell Engagers (TCEs) link immune and cancer cells for enhanced efficacy. Optimizing TCE binding kinetics and target properties maximizes the formation of the drug-target trimer in the tumor microenvironment (TME).
Area of Science:
- Immunology
- Pharmacology
- Computational Biology
Background:
- T Cell Engagers (TCEs) are a novel immuno-oncology therapy bypassing antigen presentation.
- TCE efficacy relies on simultaneous binding to both immune and cancer cells within the tumor microenvironment (TME).
- Maximizing the formation of the drug-target trimer is crucial for enhancing TCE therapeutic effects.
Purpose of the Study:
- To quantitatively investigate how TCE design and target properties influence ternary complex concentration and biodistribution.
- To explore the impact of binding kinetics on TCE efficacy.
- To assess the utility of pre-clinical data for estimating TCE binding affinities.
Main Methods:
- Development of a simplified mathematical model for drug-target interactions, inspired by the "three-body" problem.
- Application of parameter identifiability analysis to steady-state data.
- Analysis of kinetic features of existing clinical and developmental TCE antibodies.
- Evaluation of a quantitative pharmacology model incorporating peripheral drug disposition.
Main Results:
- Steady-state data is sufficient for estimating TCE binding affinity to both targets.
- The study identified common kinetic features among various TCE antibodies.
- The model provides insights into optimizing TCE design for improved efficacy.
Conclusions:
- Mathematical modeling is a valuable tool for understanding and optimizing T Cell Engager therapies.
- Binding kinetics and target properties significantly impact TCE performance in the TME.
- This research supports the development of more effective immuno-oncology treatments.
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