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Dwivedi et al., (2014). A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development.

September 2014, model of the month by Vincent Knight-Schrijver
Original models: BIOMD0000000534, BIOMD0000000535, BIOMD0000000536 and BIOMD0000000537


Introduction

Cytokines are essential protein elements of cell-mediated immune signalling. Dysfunctional regulation of cytokines, including interleukins, can lead to pathogenesis of autoimmune diseases and chronic inflammatory conditions. The cytokine IL-6 is a significant player in the pathogenesis of various autoimmune diseases including Diabetes, Alzheimer's and Atherosclerosis. Recently, the pathological activity of IL-6 in inflammatory bowel disease (IBD) and Crohn's has been also been demonstrated. Evidence suggests that IL-6 facilitates T-cell accumulation by attenuating apoptosis and that the resulting inflammation is reversible by IL-6 inhibition (Mudter and Neurath, 2007)[1]. With apparent benefit observed, the development of an anti-IL-6 agent provides a potential therapy, but which protein should we target?


Model

The model by Dwivedi et al., (2014) [2] is comprised of 4 similarly constructed models with different ligands and initial conditions:

  1. [BIOMD0000000534] Healthy patient model - used to validate model dosage and administration kinetics.
  2. [BIOMD0000000535] Crohn's Disease model - activity of an anti-IL-6 antibody.
  3. [BIOMD0000000536] Crohn's Disease model - activity of sgp130, an endogenous inhibitor of soluble Il-6/IL-6R.
  4. [BIOMD0000000537] Crohn's Disease model - activity of anti-IL-6 receptor antibody.

Dwivedi et al analyse antibody activity by targeting either the IL-6 ligand or the IL-6 receptor and comparing their pharmacological effects. Two hypothetical antibodies with identical kinetic parameters were assessed as well as an sgp130 (soluble glycoprotein 130 (gp130)) mimetic antibody and the clinical anti-IL-6R agent Tocilizumab. IL-6 signalling is mediated via two major pathways, JAK/STAT and MAPK, compared neatly in a previous model (Singh et al ., (2006) [3, BIOMD0000000151]). For this model's purposes, the JAK/STAT pathway is utilised and the STAT3 phosphorylation cascade is simplified to a single step and the resulting signalling framework and compartmental structure are illustrated in Figure 1 below. The biomarker observed here is the ubiquitous C-Reactive Protein (CRP) which is elevated in many inflammatory conditions. Its expression is controlled by pSTAT3 activity, hence its utility here as measure of IL-6 inhibition.

Figure 1

Figure 1.A diagrammatic representation of the model with (a) IL-6 transduction events, IL-6 binds to the membrane or soluble receptor. This complex subsequently binds to membrane bound gp130 and the resulting heterotrimer also dimerises creating an active IL-6 hexameric complex, (b) simplified STAT3 signalling (b) and (c) compartmentalised structure. A peripheral compartment (not shown here) is also included to represent off-target tissue distribution of the antibody. Figure taken from [2].

Results

The simulations were carried out from steady state. The model successfully, albeit not to scale, mimics the suppression profile of CRP seen in experimental tocilizumab patients with biweekly and bimonthly dosage regimens (Figure 3 in original paper[2]). Simulation comparing antibody targets indicates that targeting IL-6 produces a typical graded response (Figure 2b) whilst inhibition of IL-6Ra produces suppression in a switch-like manner (Figure 2e). Both receptor and ligand inhibition is capable of achieving maximal CRP suppression after 12 weeks at a high enough dose with reduction in CRP by > 90% at 300 mg (Figure 2b, 2e).

Figure 2

Figure 2.Time course and dose response simulations with IV dosing at 4 week intervals over a twelve week period. Concentrations of serum CRP and IL-6, and gut pSTAT3 and IL-6 at a dose of 300 mg targeting either (a) IL-6 and (d) IL-6Ra. With three antibody binding affinities, the CRP suppression after 12 weeks was measured targeting either (b) IL-6 or (e) IL-6Ra. Time courses (c) and (f) show serum antibody kinetics with IV administration for IL-6 and IL-6Ra respectively. Figure taken from [2]

Using extra reactions, the model can also explore additional non-competitive binding or allosteric inhibition, allowing the antibody to bind to the IL6/IL6Ra complex (Figure 5 in original paper [2]). An increase in potency was seen with the anti-IL6 antibody at high affinity values but not with the anti-IL6Ra antibody when targetting the complex was included.

The CRP suppression of a final ligand sgp130FC (an anti-IL6:IL-6Ra antibody construct of sgp130 and IgG) was assessed (Figure 3). They assume that sgp130FC retained the binding capabilities of sgp130; even at considerable 2 g doses at 1 week intervals, sgp130FC fails to suppress CRP fully.

Figure 3

Figure 3.Simulated suppression of CRP after 12 weeks administration of sgp130FC. Three different dosing regimens were used with intervals at: 1 (Q1W); 2 (Q2W) and 4 (Q4W) weeks. Figure taken from [2].


Conclusion

Comparison between the antibody targets highlights a key difference in response. The switch-like response that the anti-IL6Ra antibody elicited (Figure 2e) could be due to sequestration of the antibody by the soluble receptor. The author discusses that IL6 signalling is thus only affected once the antibody overwhelms the soluble receptor population.

Demonstrating a multi-compartmental system, this framework can be similarly utilised in other areas for pharmacological analyses. To be used as predictive evidence, this model illustrates the use of a systems pharmacology approach to compare the therapeutic effect of targeting different components in the same signalling pathway. Which is the most effective target? The results of an approach like this can be used to inform and strategise for future drug development.

References

  1. Mudter and Neurath. Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm Bowel Dis. 2007 Aug;13(8):1016-23
  2. Dwivedi et al. A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development. CPT Pharmacometrics Syst Pharmacol. 2014 Jan 8;3:e89.
  3. Singh et al. Modeling regulatory mechanisms in IL-6 signal transduction in hepatocytes. Biotechnol. Bioeng. 2006 Dec; 95(5): 850-862
  4. Dirks and Meibohm. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010 Oct;49(10):633-59.
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