Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling.
Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling.
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DOI：
10.3389/fimmu.2022.919489
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发表时间：
2022
影响因子：
7.3
通讯作者：
Klein B
中科院分区：
文献类型：
--
作者：
Rossi JF;Chiang HC;Lu ZY;Levon K;van Rhee F;Kanhai K;Fajgenbaum DC;Klein B
调节异常的白细胞介素（IL）-6的产生可以通过存在的水平，其上升的动力学和其不适当的位置来表征。快速、过量的IL-6产生会加剧重要器官的组织损伤。在这种情况下，抗IL-6或抗IL-6受体（IL-6 R）单克隆抗体治疗，如果剂量不当，可能不足以完全阻断IL-6信号传导并使免疫应答正常化。我们分析了分别接受托珠单抗（抗IL-6 R）或司妥昔单抗（抗IL-6）治疗的COVID-19或特发性多中心Castleman病（iMCD）患者的C反应蛋白（CRP）抑制情况--IL-6活性的生物标志物。我们使用数学建模来分析如何针对这些疾病中观察到的高水平IL-6优化抗IL-6或抗IL-6 R阻断。在接受标准剂量抗IL-6治疗的COVID-19或iMCD患者中，IL-6信号传导抑制不充分。在整个治疗过程中病情恶化的患者仅部分抑制CRP的产生。我们的模型表明，在代表iMCD的情况下，持续高IL-6产生不受单剂量抗IL-6治疗的控制，重复给药更有效地抑制IL-6活性。在快速、高、失调的IL-6产生的情况下，如严重的COVID-19或细胞因子风暴，每天重复施用抗IL-6/抗IL-6 R药物，或每天交替施用抗IL-6和抗IL-6 R治疗，可以中和IL-6活性。在临床实践中，IL-6抑制应根据病理生理学进行个体化，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siltuximab II期临床数据的分析。
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.
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影响因子：
8.8
作者：
McArdle, PA;McMillan, DC;Underwood, MA
通讯作者：
Underwood, MA
影响因子：
3.8
作者：
LU, ZY;BRAILLY, H;KLEIN, B
通讯作者：
KLEIN, B
影响因子：
2.9
作者：
Paccaly AJ;Kovalenko P;Parrino J;Boyapati A;Xu C;van Hoogstraten H;Ishii T;Davis JD;DiCioccio AT
通讯作者：
DiCioccio AT
影响因子：
51.1
作者：
van Rhee, Frits;Wong, Raymond S.;Casper, Corey
通讯作者：
Casper, Corey
DOI：
10.1111/j.1432-1033.1988.tb14384.x
发表时间：
1988-11-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
CASTELL, JV;GEIGER, T;HEINRICH, PC
通讯作者：
HEINRICH, PC