Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling

• Published in: Frontiers in immunology Vol. 13; p. 919489
• Main Authors: Rossi, Jean-François, Chiang, Hao-Chun, Lu, Zhao-Yang, Levon, Kalle, van Rhee, Frits, Kanhai, Karan, Fajgenbaum, David C, Klein, Bernard
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers 19.07.2022; Frontiers Media S.A
• Subjects: C-Reactive Protein; C-Reactive Protein - therapeutic use; Castleman Disease; Castleman Disease - drug therapy; COVID-19; COVID-19 Drug Treatment; Cytokine Release Syndrome; cytokine storm; Humans; idiopathic multicentric castleman disease; Immunology; Life Sciences; mathematic model; Precision Medicine; siltuximab; COVID-19; siltuximab; tocilizumab; C-reactive protein; cytokine storm; idiopathic multicentric castleman disease; interleukin-6; mathematic model
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.919489

Dysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response. We analysed inhibition of C-reactive protein (CRP) - a biomarker for IL-6 activity - in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases. IL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity. In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production. EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.