Hématologie-Immunothérapie, Institut du Cancer Avignon-Provence, Sainte Catherine, Avignon, France.
Faculté de Médecine Montpellier, Université de Montpellier, Montpellier, France.
Front Immunol. 2022 Jul 19;13:919489. doi: 10.3389/fimmu.2022.919489. eCollection 2022.
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.
白细胞介素（IL）-6 产生失调的特征可以是存在水平、其升高的动力学及其位置不当。快速、过度的 IL-6 产生会加剧重要器官的组织损伤。在这种情况下，如果剂量不当，使用抗 IL-6 或抗 IL-6 受体（IL-6R）单克隆抗体治疗可能不足以完全阻断 IL-6 信号传导并使免疫反应正常化。
我们分析了 COVID-19 或特发性多中心 Castleman 病（iMCD）患者接受托珠单抗（抗 IL-6R）或西妥昔单抗（抗 IL-6）治疗后 C 反应蛋白（CRP）的抑制情况 - IL-6 活性的生物标志物。我们使用数学模型来分析如何优化抗 IL-6 或抗 IL-6R 阻断以应对这些疾病中观察到的高水平 IL-6。
接受标准剂量抗 IL-6 治疗的 COVID-19 或 iMCD 患者的 IL-6 信号传导抑制不足。在整个治疗过程中病情恶化的患者仅部分抑制 CRP 产生。我们的模型表明，在代表 iMCD 的场景中，持续存在的高水平 IL-6 产生不受单次抗 IL-6 治疗控制，重复给药更有效地抑制 IL-6 活性。在快速、高、失调的 IL-6 产生情况下，例如严重的 COVID-19 或细胞因子风暴，每日重复给予抗 IL-6/抗 IL-6R 药物，或交替每日给予抗 IL-6 和抗 IL-6R 治疗，可中和 IL-6 活性。
在临床实践中，应根据病理生理学个体化进行 IL-6 抑制，以实现 CRP 产生的完全阻断。
EUSA Pharma 资助了医学写作援助，并提供了西妥昔单抗的 II 期临床数据供分析。
