A mathematical modelling tool for unravelling the antibody-mediated effects on CTLA-4 interactions

Aravindhan Ganesan,Theinmozhi Arulraj,Tahir Choulli,Khaled H Barakat

doi:10.1186/s12911-018-0606-x

Aravindhan Ganesan, Theinmozhi Arulraj + Show 2 more

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https://doi.org/10.1186/s12911-018-0606-x

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Abstract

BackgroundMonoclonal antibodies blocking the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor have revolutionized the field of anti-cancer therapy for the last few years. The human T-cell-based immune responses are modulated by two contradicting signals. CTLA-4 provides a T cell inhibitory signal through its interaction with B7 ligands (B7–1 and B7–2), while CD28 provides a stimulatory signal when interacting with the same ligands. A previous theoretical model has focused on understanding the processes of costimulatory and inhibitory complex formations at the synapse. Nevertheless, the effects of monoclonal antibody (mAb)-mediation on these complexes are relatively unexplored. In this work, we expand on the previous model to develop a new mathematical framework for studying the effects of anti-CTLA-4 mAbs on the co-stimulatory (CD28/B7 ligands) and the co-inhibitory (CTLA-4/B7 ligands) complex formation at the immunological synapse. In particular, we focus on two promising anti-CTLA-4 mAbs, tremelimumab (from AstraZeneca) and ipilimumab (from Bristol-Myers Squibb), which are currently in clinical trials and the market, respectively, for targeting multiple tumors.MethodsThe mathematical model in this work has been constructed based on ordinary differential equations and available experimental binding kinetics data for the anti-CTLA-4 antibodies from literature.ResultsThe numerical simulations from the current model are in agreement with a number of experimental data. Especially, the dose-curves for blocking the B7 ligand binding to CTLA-4 by ipilimumab are comparable with the results from a previous competitive binding assay by flow cytometry and ELISA. Our simulations predict the dose response and the relative efficacies of the two mAbs in blocking the inhibitory CTLA-4/B7 complexes.ConclusionsThe results show that different factors, such as multivalent interactions, mobility of molecules and competition effects, could impact the effects of antibody-mediation. The results, in particular, describe that the competitive effects could impact the dose-dependent inhibition by the mAbs very significantly. We present this model as a useful tool that can easily be translated to study the effects of any anti-CTLA-4 antibodies on immunological synaptic complex formation, provided reliable biophysical data for mAbs are available.

Highlights

Monoclonal antibodies blocking the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor have revolutionized the field of anti-cancer therapy for the last few years
A second signal comes from the binding of CD28, a coreceptor expressed on the T-cell surface, with its’ complementary B7 ligands, known as B7–1 and B7–2, on the surface of antigen-presenting cells (APCs)
We studied how the binding of Monoclonal antibodies (mAbs) to CTLA-4 dynamically changed the interactions among co-inhibitory complexes (CTLA-4/B7–1 and CTLA-4/B7–2) and co-stimulatory complexes

Summary

Introduction

Monoclonal antibodies blocking the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor have revolutionized the field of anti-cancer therapy for the last few years. The human T-cell-based immune responses are modulated by two contradicting signals. A previous theoretical model has focused on understanding the processes of costimulatory and inhibitory complex formations at the synapse. We expand on the previous model to develop a new mathematical framework for studying the effects of anti-CTLA-4 mAbs on the co-stimulatory (CD28/B7 ligands) and the coinhibitory (CTLA-4/B7 ligands) complex formation at the immunological synapse. There are a number of negative signal stimuli (known as the inhibitory receptors) that act to inactivate the T-cells, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4 or CD152) and programmed death 1 (PD1 or CD279) [3]. CTLA-4, a CD28 homologue (with ~ 30% sequence identity) expressed on the T-cell surface, binds with the same set of B7-ligands of CD28; albeit with higher affinity towards B7–1 and

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