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Simulation of Rituximab and Natalizumab biomarker efficacy using simplified QSP model of B- and T- lymphocyte dynamics in Multiple Sclerosis
EP39285
Poster Title: Simulation of Rituximab and Natalizumab biomarker efficacy using simplified QSP model of B- and T- lymphocyte dynamics in Multiple Sclerosis
Submitted on 14 Sep 2022
Author(s): Anna Mishina (1,2), Tatiana Karelina (1), Evgeny Metelkin (1), Veronika Musatova (1)
Affiliations: (1) InSysBio LLC, Moscow, Russia; (2) Skolkovo Institute of Science and Technology, Moscow, Russia
This poster was presented at PAGE 2022
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Poster Information
Abstract: Introduction: Immune-mediated disease affecting the CNS, multiple sclerosis (MS), is the leading cause of neurological disability among people aged from 20 to 50. The etiology and pathogenesis of MS have been being addressed for more than 70 years, nevertheless, a consensus has not yet been reached. Intriguingly, recent observations of the high efficiency of anti-CD20 and anti-VLA-4 therapies (Rituximab and Natalizumab, respectively) have revealed an important B cells’ role, independent of antibody production, in MS development (1). Moreover, the latter-day study provided robust evidence that the interaction of B and T cells subsequently leads to T-cells activation and expansion, being an important driver of autoimmune response in MS (2). Such findings could possibly serve as a basis for creating a currently lacking comprehensive mechanistic MS model capable of predicting different therapies' effects.

Objectives: The goal of this work was to utilize latest findings on the interaction between B and T-cells for development of a quantitative systems pharmacology (QSP) model that describes key processes contributing to lymphocyte dynamics in MS and targeted by currently investigated therapies.

Methods: We suggest the 2-compartment (Plasma and CNS, central nervous system) ODE model, which includes key cellular processes such as apoptosis, proliferation, migration, and, most importantly, B-T cells interaction with subsequent T cell activation, based on the following finding that self-reactive brain-homing effector-memory (EM) CD4+ T cells are proliferated upon interaction with memory B cells (2). Two parameters distinguishing patients from healthy subjects are k_act (rate constant of activation of naive T cells into EM T cells and which is dependent on memory B cell concentration in plasma) and Eff_T_B (additive factor responsible for memory B cells proliferation in response to EM T cells abundance). These parameters for MS and HD cohorts were estimated based on the data of the autoproliferation assay (3) from both groups. Then, scoping the literature and databases, we found the materials to extract values of some other parameters including rates of proliferation, apoptosis and migration that were further kept fixed in the model (4,5). After that, the model was calibrated on the published data containing cell numbers of needed lymphocyte subtypes in blood and CSF in HD and MS patients. Finally, we examined the model performance by introducing mechanistically effects of Natalizumab and Rituximab. To reproduce the effect of Natalixumab, anti-VLA-4 monoclonal antibody that prevents lymphocytes from migration to CNS, we set migration rate constants of memory B cells and EM T cells to null. In regards to Rituxumab, B cell depleting therapy, we simulated its mechanism of action by setting memory B cells concentration to null. All used datasets (6–8) consist of data from MS diagnosed patients with relapse-remitting (RRMS) disease course, and measurement of T and/or B cells was conducted twice: before and after 24 weeks of treatment. Qualitative comparison of simulated dynamics to clinical trials allowed us to conclude about the model performance.

Results: The current QSP model of MS describes the difference between CNS T cell accumulation in healthy and MS subjects. It recapitulates the major effects on lymphocyte pools in blood and CSF observed in clinical trials of Natalizumab and Rituximab. Simulation of B cell depletion in the plasma leads to subsequent reduction in T cells abundance in both CNS and plasma compartments. These findings correspond to the observations from clinical trials of Rituximab therapy applied to MS cohort (6). Natalizumab treatment results in increased numbers of B and T lymphocytes in plasma and depleted concentrations of them in CSF. These dynamics were reproduced in our model upon switching migration to zero.

Conclusion: Taking as the basis the recent finding that B cells play a central role in MS pathogenesis via antigen-presentation with the following activation of T cells, we built the QSP model capable of predicting therapies-driven cell dynamics. Therefore, this simple model describes major contributors to MS relapses and could serve as the groundwork for more expanded neuroimmune MS models with capabilities relevant to current drug research and development.

Summary: Taking as the basis the recent finding that B cells play a central role in MS pathogenesis via antigen-presentation with the following activation of T cells, we built the QSP model capable of predicting therapies-driven cell dynamics. Therefore, this simple model describes major contributors to MS relapses and could serve as the groundwork for more expanded neuroimmune MS models with capabilities relevant to current drug research and development.References: Greenfield, A. L. & Hauser, S. L. B Cell Therapy for Multiple Sclerosis: Entering an Era. Ann. Neurol. 83, 13–26 (2018).
Jelcic, I. et al. Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis. Cell 175, 85-100.e23 (2018).
Mohme, M. et al. HLA-DR15-derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis. Brain 136, 1783–1798 (2013).
Nishihara, H. et al. Human CD4+ T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro. Fluids Barriers CNS 17, 3 (2020).
Immune Response Template. Immune Response Template https://irt.insysbio.com/.
Cross, A. H., Stark, J. L., Lauber, J., Ramsbottom, M. J. & Lyons, J.-A. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J. Neuroimmunol. 180, 63–70 (2006).
Cuculiza Henriksen, A. et al. Natalizumab differentially affects plasmablasts and B cells in multiple sclerosis. Mu
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