Tocilizumab, as a humanised monoclonal antibody, can target both membrane-bound and soluble forms of the IL-6 receptor.[1] Tocilizumab has been approved for treatment in patients with rheumatologic disorders and chimeric antigen receptor T cell-induced cytokine release syndrome.[3]
In vitro efficacy test it shown that treatment with tocilizumab (1 or 10 μm) or SOMAmer (0.83 or 8.3 μm), SOMAmer suppressed the proliferation of U87MG and HepG2 cells to a greater extent than tocilizumab at similar molar concentrations.[7]
In vivo efficacy test it indicated that treatment with 8 mg/kg tocilizumab using two consecutive intravenous infusions 12 h apart in 100 patients with COVID-19 and ARDS requiring ventilatory support in Brescia (Italy) has 20% mortality according to an optional third infusion based on clinical response.[1] In vivo, tocilizumab 8 mg/kg?×?1 in mechanically ventilated patients, the results shown that receipt of tocilizumab was independently associated with improved survival.[2] In vivo study for the treatment of rheumatoid arthritis, treatment with 4?mg/kg tocilizumab, the results exhibited that the average IL-6 level reached the peak at the second week after administration, and then decreased gradually.[4] In a 61-year-old man with COVID-19, treatment with 324 mg Tocilizumab via subcutaneous with hydroxychloroquine can successfully manage the infection.[6] In addition, the recommended dose of Tocilizumab is 4–8 mg/kg administered as a single 60- minute intravenous infusion every 4 weeks for treatment in moderate to severe active arthritis in adults, Giant cell arthritis, Polyarticular juvenile idiopathic arthritis and cytokine release syndrome in patients 2 years of age older with active disease.[5]
参考文献:
[1] Lan SH, et al. Tocilizumab for severe COVID-19: a systematic review and meta-analysis. Int J Antimicrob Agents. 2020 Sep;56(3):106103.
[2]Somers EC, et al. Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19. Clin Infect Dis. 2021 Jul 15;73(2):e445-e454.
[3]Wei Q, et al. Tocilizumab treatment for COVID-19 patients: a systematic review and meta-analysis. Infect Dis Poverty. 2021 May 18;10(1):71.
[4]Smolen J.S, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.?Lancet.?2008;371(9617):987–997.
[5]Sebba A, et al. Tocilizumab: the first interleukin -6 receptor inhibitor.?Am J Health Syst Pharm.?2008;65(15):1413–1418. ?
[6]Fontana F, et al. Covid-19 pneumonia in a kidney transplant recipient successfully treated with Tocilizumab and Hydroxychloroquine.?Am. J. Transplant. American J. Transplant.?2020;20(7).
[7]Gupta S, et al. Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor. J Biol Chem. 2014 Mar 21;289(12):8706-19.
Tocilizumab 作为一种人源化单克隆抗体，可以靶向 IL-6 受体的膜结合和可溶形式。[1] Tocilizumab 已被批准用于治疗风湿病和嵌合体疾病患者抗原受体T细胞诱导的细胞因子释放综合征。[3]
体外功效测试表明，在相似的摩尔浓度下，用托珠单抗（1 或 10 μm）或 SOMAmer（0.83 或 8.3 μm）处理时，SOMAmer 比托珠单抗更能抑制 U87MG 和 HepG2 细胞的增殖。[7]
体内疗效测试表明，在布雷西亚（意大利）需要通气支持的 100 名 COVID-19 和 ARDS 患者中，使用间隔 12 小时连续两次静脉输注 8 mg/kg tocilizumab 的死亡率为 20%，根据可选的根据临床反应进行第三次输注。[1] 在机械通气患者体内，tocilizumab 8 mg/kg‰×‰1，结果显示接受 tocilizumab 与改善生存独立相关。[ 2] 治疗类风湿性关节炎的体内研究，4?mg/kg tocilizumab治疗，结果显示平均IL-6水平在给药后第二周达到峰值，然后逐渐下降。< sup>[4] 在一名患有 COVID-19 的 61 岁男性中，通过皮下注射 324 mg 托珠单抗和羟氯喹可以成功控制感染。[6] 此外，托珠单抗的推荐剂量为 4-8 mg/kg，单次给药每 4 周静脉输注 60 分钟，用于治疗成人中度至重度活动性关节炎、巨细胞性关节炎、多关节幼年特发性关节炎和 2 岁以上活动性疾病患者的细胞因子释放综合征。[5]
| Cell experiment [1]: | |
|
Cell lines |
U266B1 cells |
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Preparation Method |
Cell Proliferation Assays U266B1 cells were suspended with SOMAmer (1, 10, or 100 μg/ml) or tocilizumab (1, 10, or 100 μg/ml) in RPMI 1640 medium containing 10% FBS at 104 cells per well and cultured for 30 min at 37 °C in a 5% CO2 incubator. |
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Reaction Conditions |
1, 10, or 100 μg/ml，30 min at 37 °C |
|
Applications |
SL1026 achieved complete inhibition of IL-6 at 1 μg/ml (83 nm), whereas tocilizumab achieved 60% inhibition at a roughly equivalent molar concentration (67 nm) . |
| Animal experiment [2]: | |
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Animal models |
Patients with rheumatoid arthritis |
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Preparation Method |
Patients (n=1262) were randomised 1:1 to receive Tocilizumab-SC 162?mg weekly (qw)+placebo-IV every four?weeks (q4w) or Tocilizumab-IV 8?mg/kg q4w+placebo-SC qw in combination with DMARD(s). Maintenance of clinical responses and safety through week 97 were assessed. |
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Dosage form |
8?mg/kg; SC,IV |
|
Applications |
Tocilizumab-SC had a comparable safety profile to Tocilizumab-IV through week 97, except that injection site reactions (ISRs) were more common with Tocilizumab-SC. Safety profiles in patients who switched were similar to those in patients who received continuous Tocilizumab-SC or Tocilizumab-IV treatment. |
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参考文献: [1]. [1]Gupta S, et al. Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor. J Biol Chem. 2014 Mar 21;289(12):8706-19. [2]. Burmester GR, et al. Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA). Ann Rheum Dis. 2016 Jan;75(1):68-74.? |
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